Changes in the Peripheral Blood mtDNA Levels in Naive Patients Treated by Different Nucleoside Reverse Transcriptase Inhibitor Combinations and Their Association with Subsequent Lipodystrophy

Abstract

Nucleoside reverse transcriptase inhibitors (NRTIs) differ in the type and severity of adverse effects resulting from mitochondrial abnormalities. mtDNA in peripheral blood mononuclear cells (PBMCs) was measured during the first 12 months of different NRTIs combinations and its association with clinical lipodystrophy was estimated. Extended follow-up of a randomized trial, ALBI-ANRS 070, including antiretroviral naive patients was conducted. Total DNA was extracted from available cryopreserved PBMCs at baseline and months 6 and 12. Nuclear and mitochondrial genes were amplified using a real-time PCR assay. Clinical lipodystrophy was assessed 30 months after randomization using a standardized questionnaire. A logistic regression analysis assessed the value of mtDNA to predict lipodystrophy. Mean mtDNA level (copies/cell) significantly decreased from 5847 at baseline to 3176 at month 12 (p < 0.0001). In the zidovudine + lamivudine (ZDV + 3TC) arm (n = 37), the mean mtDNA was 6098, 6807, and 3725 copies/cell for baseline, month 6, and month 12, respectively. In the stavudine + didanosine (d4T + ddI) arm (n = 40), the mean values were 5616, 5731, and 2648 copies/cell, respectively. The proportion of patients in the lowest quartile of mtDNA (<1421 copies/cell) at month 12 was higher in 18 patients with lipodystrophy (44%) than in 28 without lipodystrophy (7%) (p = 0.008). At 12 months, a larger reduction of mtDNA from baseline was observed in those started on the d4T + ddI arm. Furthermore, a low mtDNA level at month 12 was associated with the subsequent development of lipodystrophy. This marker may be of value for the early prevention of lipodystrophy in treated HIV-infected patients.

Possible Mitochondrial Dysfunction and Its Association with Antiretroviral Therapy Use in Children Perinatally Infected with HIV

“…Other in vitro and in vivo studies have provided evidence of differential effects of NRTIS and combinations [14-17, 23, 43, 49]. Our study provides support for these studies demonstrating different potentials of individual NRTIs to affect mitochondria [41, 46], and that specific NRTIs in combination may affect mitochondrial function differently than may be predicted by a single NRTI, (e.g.…”

“…Clinical signs and symptoms of MD may not be recognized in advanced HIV disease with marked elevations of HIV viral load treated with multiple antiretroviral medications. Expression of MD may be related to host mitochondrial haplotypes or other genetic characteristics [10, 11], defects in intergenomic communication such as mitochondrial DNA depletion syndromes [12], environmental influences including HIV infection [13, 14], and specific ARVs [14-17]. Mitochondrial toxicity due to NRTI use in HIV-infected adults has been reported with zidovudine (ZDV), lamivudine (3TC), and stavudine (d4T) [4, 17-23], and in children with didanosine (ddI) exposure [24, 25].…”

Improvement of Mitochondrial Toxicity in Patients Receiving a Nucleoside Reverse‐Transcriptase Inhibitor–Sparing Strategy: Results from the Multicenter Study with Nevirapine and Kaletra (MULTINEKA)

“…The measurement of mitochondrial DNA and its function in PBMCs may be of value for the early prevention of these toxicities in treated patients with HIV infection. A significant number of studies have shown the association between the use of NRTIs and mtDNA depletion, as well as the association between low mtDNA levels and subsequent development of lipodystrophy in patients with HIV infection [2,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. On the other hand, it has also been suggested that mtDNA content in peripheral blood cells may not be an accurate biomarker of mitochondrial toxicity in lipoatrophic adipose tissue because of a poor correlation between this parameter and any other mitochondrial parameter, as well as because of the preservation of mtDNA-dependent mitochondrial functions despite severe mtDNA depletion [34][35][36][37].…”

Toxicidad de fármacos antirretrovirales en niños infectados por el virus de la inmunodeficiencia humana

“…El caso 1 es un caso típico de una adolescente de 13 años con infección, con exposición acumulativa y prolongada a TARGA y con el agravante, como en otros casos históricos cuando escaseaban los antirretrovirales, del empleo habitual de fármacos más tóxicos como asociación d4T + ddI, que era la regla. Se ha descrito que los fenómenos más graves de lipodistrofia morfológica se asocian con la mayor duración del TARGA, con la pubertad y con el uso de d4T [19][20][21] , todos ellos presentes en nuestra paciente. En este caso, a pesar de realizar medidas higiénico-dietéticas y modificaciones de los antirretrovirales, llegando incluso a la interrupción del mismo, precisó finalmente fármacos hipolipidemiantes.…”