Improvement of mitochondrial toxicity in patients receiving a nucleoside reverse-transcriptase inhibitor-sparing strategy: results from the Multicenter Study with Nevirapine and Kaletra (MULTINEKA).
BACKGROUND
Nucleoside reverse-transcriptase inhibitor (NRTI)-related mitochondrial toxicity has been suggested as a key factor in the induction of antiretroviral-related lipoatrophy. This study aimed to evaluate in vivo the effects of NRTI withdrawal on mitochondrial parameters and body fat distribution.


METHODS
A multicenter, prospective, randomized trial assessed the efficacy and tolerability of switching to lopinavir-ritonavir plus nevirapine (nevirapine group; n = 34), compared with lopinavir-ritonavir plus 2 NRTIs (control group; n = 33) in a group of human immunodeficiency virus-infected adults with virological suppression. A subset of 35 individuals (20 from the nevirapine group and 15 from the control group) were evaluated for changes in the mitochondrial DNA (mtDNA) to nuclear DNA ratio and cytochrome c oxidase (COX) activity after NRTI withdrawal. Dual-energy X-ray absorptiometry (DEXA) scans were used to objectively quantify fat redistribution over time.


RESULTS
The nevirapine group experienced a progressive increase in mtDNA content (a 40% increase at week 48; P = .039 for comparison between groups) and in the COX activity (26% and 32% at weeks 24 and 48, respectively; P = .01 and P = .09 for comparison between groups, respectively). There were no statistically significant between-group differences in DEXA scans at week 48, although a higher fat increase in extremities was observed in the nevirapine group. No virologic failures occurred in either treatment arm.


CONCLUSIONS
Switching to a nucleoside-sparing regimen of nevirapine and lopinavir-ritonavir maintained full antiviral efficacy and led to an improvement in mitochondrial parameters, which suggests a reversion of nucleoside-associated mitochondrial toxicity. Although DEXA scans performed during the study only revealed slight changes in fat redistribution, a longer follow-up period may show a positive correlation between reduced mitochondrial toxicity and a clinical improvement of lipodystrophy.
Negredo
Eugenia
E
Lluita contra la SIDA Foundation, Barcelona, Spain. enegredo@flsida.org
Miró
Oscar
O
Rodríguez-Santiago
Benjamí
B
Garrabou
Glòria
G
Estany
Carla
C
Masabeu
Angels
A
Force
Lluís
L
Barrufet
Pilar
P
Cucurull
Josep
J
Domingo
Pere
P
Alonso-Villaverde
Carlos
C
Bonjoch
Anna
A
Morén
Constanza
C
Pérez-Alvarez
Núria
N
Clotet
Bonaventura
B
D015502:Absorptiometry, Photon; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D001823:Body Composition / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000032:analysis*; D004359:Drug Therapy, Combination; D003576:Electron Transport Complex IV / Q000378:metabolism; D005121:Extremities; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism; D039682:HIV-Associated Lipodystrophy Syndrome / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008055:Lipids / Q000097:blood; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000627:therapeutic use; D011744:Pyrimidinones / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D019438:Ritonavir / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D008055:Lipids; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D061466:Lopinavir; D019829:Nevirapine; D003576:Electron Transport Complex IV; D019438:Ritonavir