Mitochondrial changes during D-drug-containing once-daily therapy in HIV-positive treatment-naive patients.
BACKGROUND
Antiviral drugs of the category of nucleoside reverse transcriptase inhibitors (NRTIs), largely used for the treatment of HIV infection, can have toxic effects on mitochondria. We performed a cross-sectional study on mitochondrial toxicity in a randomized group of patients belonging to a larger randomized study on different NRTI-based once-daily regimens by quantifying mitochondrial DNA (mtDNA), three different mitochondrial RNAs (mtRNAs) and functional parameters in highly purified peripheral CD4+ and CD8+ T-cells.


METHODS
A total of 49 previously treatment-naive patients treated for a mean of 15 months with efavirenz plus didanosine plus lamivudine (group 1), or tenofovir disoproxil fumarate plus lamivudine (group 2), or didanosine plus abacavir (group 3) were considered. The groups were matched for sex, age, CDC classification, risk factor for HIV, nadir CD4+ T-cell count and baseline viral load. mtDNA and mtRNA were quantified by using real-time PCR assays.


RESULTS
No patient showed any clinical symptom; however, the amount of mtDNA in CD4+ and CD8+ T-cells was significantly lower in groups 1 and 3; similarly, the expression of different mtRNAs in both CD4+ and CD8+ T-cells showed significant differences that were dependent upon the drug used. No differences were found in mitochondrial membrane potential and mitochondrial mass in peripheral lymphocytes. The amount of total HIV DNA in CD4+ T-cells did not differ among the groups, who displayed a similar immune reconstitution and control of the virus.


CONCLUSIONS
An efficient didanosine-containing once-daily therapy can have more mitochondrial toxicity than regimens devoid of this drug.
Maggiolo
Franco
F
Unit of Antiviral Therapy, Division of Infectious Diseases, Ospedali Riuniti, Bergamo, Italy.
Roat
Erika
E
Pinti
Marcello
M
Nasi
Milena
M
Gibellini
Lara
L
De Biasi
Sara
S
Airoldi
Monica
M
Ravasio
Veronica
V
Mussini
Cristina
C
Suter
Fredy
F
Cossarizza
Andrea
A
D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000328:Adult; D000480:Alkynes; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines / Q000008:administration & dosage / Q000009:adverse effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D003430:Cross-Sectional Studies; D003521:Cyclopropanes; D004272:DNA, Mitochondrial / Q000032:analysis / Q000235:genetics; D016049:Didanosine / Q000008:administration & dosage / Q000009:adverse effects; D015224:Dideoxynucleosides / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D006678:HIV / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000821:virology; D063065:Organophosphonates / Q000008:administration & dosage / Q000009:adverse effects; D012313:RNA / Q000032:analysis / Q000235:genetics; D000077278:RNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000068698:Tenofovir; D000099227:Abacavir
D000225:Adenine; D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D004272:DNA, Mitochondrial; D016049:Didanosine; D015224:Dideoxynucleosides; D019259:Lamivudine; D063065:Organophosphonates; D012313:RNA; D000077278:RNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000099227:Abacavir; C098320:efavirenz