Greater and more rapid depletion of mitochondrial DNA in blood of patients treated with dual (zidovudine+didanosine or zidovudine+zalcitabine) vs. single (zidovudine) nucleoside reverse transcriptase inhibitors.
BACKGROUND
Most toxicities associated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) are thought to result from mitochondrial toxicity. These toxicities include peripheral neuropathy, pancreatitis, lactic acidosis, and peripheral lipoatrophy. Unfortunately, there are no validated laboratory markers for clinically assessing, let alone predicting, the onset of mitochondrial toxicity associated with NRTI therapy.


OBJECTIVE
To provide preliminary evidence of the potential clinical utility of an assay which has been developed for quantifying mitochondrial DNA (mtDNA) in clinical samples from HIV-infected patients.


METHODS
A single-tube duplex real-time DNA-nucleic acid sequence-based amplification (NASBA) assay (Mitox, Primagen, Amsterdam, the Netherlands) was used to quantify mtDNA in cryopreserved peripheral blood mononuclear cells (PBMC) obtained from HIV-1-infected patients during their prior participation in a randomized placebo-controlled trial comparing zidovudine (ZDV) monotherapy with combinations of ZDV plus either dideoxycytidine (ddC) or didanosine (ddI) (the Delta trial). Patients were antiretroviral naïve prior to entering the trial. Samples obtained during the initial 48 weeks of treatment were tested.


RESULTS
A significant decline of mtDNA, both in an intent-to-treat and in an as-treated analysis, was observed in patients treated with ZDV+ddC and ZDV+ddI, but not with ZDV alone, consistent with the results expected from the degree of mtDNA depletion described for each of these drugs in vitro.


CONCLUSIONS
This single-tube duplex real-time DNA-NASBA assay was shown to measure mtDNA accurately in PBMC. Treatment with a combination of two NRTIs was associated with greater reductions in mtDNA than obtained for ZDV monotherapy. The relevance of these results in predicting treatment toxicity requires further evaluation.
Reiss
P
P
Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, University of Amsterdam, the Netherlands. p.reiss@amc.uva.nl
Casula
M
M
de Ronde
A
A
Weverling
G J
GJ
Goudsmit
J
J
Lange
J M A
JM
D000704:Analysis of Variance; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects*; D004272:DNA, Mitochondrial / Q000187:drug effects* / Q000302:isolation & purification; D016049:Didanosine / Q000008:administration & dosage / Q000009:adverse effects; D004338:Drug Combinations; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D028361:Mitochondrial Diseases / Q000139:chemically induced*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D021161:Self-Sustained Sequence Replication / Q000592:standards; D012680:Sensitivity and Specificity; D016047:Zalcitabine / Q000008:administration & dosage / Q000009:adverse effects; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D004338:Drug Combinations; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D016047:Zalcitabine; D016049:Didanosine