Impact of Nucleoside Reverse Transcriptase Inhibitors on Mitochondria in Human Immunodeficiency Virus Type 1-Infected Children Receiving Highly Active Antiretroviral Therapy

Abstract

Mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTIs) has been reported to be responsible for various adverse effects. The relative impact of NRTIs on the mitochondria of human immunodeficiency virus (HIV) type 1 (HIV-1)-infected children receiving highly active antiretroviral therapy (HAART) is unknown. 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. The median mtDNA levels in PBMCs increased from 137 copies/cell at the baseline to 179 copies/cell at week 48 (P ‫؍‬ 0.01) and 198 copies/cell at week 104 (P < 0.001). Before the initiation of HAART, children who received regimens containing didanosine had mtDNA levels persistently lower than those in children not receiving didanosine (106 versus 140 copies/cell; P ‫؍‬ 0.008). During HAART, the median increase in the mtDNA level from the baseline to week 104 was the lowest in children who received regimens containing didanosine (؉26 copies/cell) compared to those in children who received other regimens (؉79 copies/cell) (P ‫؍‬ 0.02). A multivariate analysis also demonstrated that didanosine, as part of HAART, was the only NRTI associated with the change in mtDNA levels (P ‫؍‬ 0.007). 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. This may be of particular importance in resource-limited countries where didanosine is widely used for the treatment of HIV-infected children.

Impact of Nucleoside Reverse Transcriptase Inhibitors on Mitochondrial DNA and RNA in Human Skeletal Muscle Cells

“…In agreement with our previous in vivo data (30), mtDNA significantly increased in myoblasts treated with AZT-containing regimens. Similar findings are also observed in other in vitro models, including human hepatoblastoma (HepG2) cells (5) and HSMCs (2).…”

“…We previously reported that 2Ј,3Ј-dideoxyinosine (didanosine, or ddI) significantly altered mtDNA in peripheral blood mononuclear cells (PBMCs) of HIV-1-infected children who had undetectable plasma HIV-1 RNA for more than 2 years while receiving HAART (30). This is particularly important for children, who are potentially more vulnerable than adults to the adverse effects of antiretrovirals because of their long-term exposure and the possible negative impact on growth and development (26).…”

“…The objective of this study was to investigate the effects of NRTIs, used singly and in combination, on mtDNA, mtRNA, and mRNA expression for nuclear mitochondrial regulatory factors in human skeletal muscle myoblasts and myotubes. We have specifically focused on ddI because our previous data suggested that it may be particularly deleterious to mitochondria (30). …”

Perinatal Exposure to Antiretroviral Therapy Is Associated with Increased Blood Mitochondrial DNA Levels and Decreased Mitochondrial Gene Expression in Infants

“…The initial increase may be an attempt to compensate for mitochondrial stress or dysfunction, which may also explain some of the discrepancies in the NRTI mitochondrial toxicity literature with respect to adult HIV populations, for which results have been mixed [40]. Although studies of long-term NRTI exposure in therapy-experienced patients tend to show decreased blood cell mtDNA levels [33,41,42], initial increases in blood cell mtDNA level have been observed in d4T-naive adults initiating HAART [43] and in children switching to ZDV-containing HAART [44]. It has also been suggested that early increases in mtDNA may represent a restorative phenomenon, countering the mtDNAdecreasing effect of HIV itself [43].…”

Short Communication: The Relationship Between Mitochondrial Dysfunction and Insulin Resistance in HIV-Infected Children Receiving Antiretroviral Therapy

“…[5][6][7][8][9][10] Studies have also shown an association between ARVs and mitochondrial abnormalities in HIVinfected children. 11,12 Little is known, however, regarding mitochondrial alterations in HIV-infected children with clinical evidence of insulin resistance or other metabolic complications, and whether these changes can be attributed to ARVassociated mitochondrial toxicity.…”