Partial immunological and mitochondrial recovery after reducing didanosine doses in patients on didanosine and tenofovir-based regimens.
BACKGROUND
Tenofovir disoproxil fumarate (TDF) has a safe toxicity profile; however, administration together with didanosine (ddl) increases ddl levels causing mitochondrial damage and CD4+ T-cell decline. We assessed whether a simple reduction of the ddl dose in patients receiving ddl (400 mg/day) and TDF could revert this side effect.


METHODS
Immunological and mitochondrial changes were analysed in 20 patients at baseline, after 14 months of receiving ddl (400 mg/day), TDF (300 mg/day) and nevirapine (NVP; 400 mg/day) and 14 months after a ddl dose reduction to 250 mg/day. Immunological analyses measured CD4+ and CD8+ T-cell counts and mitochondrial studies in peripheral blood mononuclear cells assessed mitochondrial DNA content by quantitative real-time PCR, cytochrome c oxidase (COX) activity by spectrophotometry and mitochondrial protein synthesis (COX-II versus beta-actin or COX-IV expression) by western blot.


RESULTS
Treatment with TDF, ddl (400 mg/day) and NVP for 14 months produced significant decreases in mitochondrial parameters and CD4+ T-cell counts. The reduction in ddl dose resulted in mitochondrial DNA recovery; however, the remaining mitochondrial parameters remained significantly decreased. Levels of CD4+ T-cells were partially restored in 35% of patients. Subjects presenting a significant reduction in CD4+ T-cells during the high ddl dose period showed greater mitochondrial impairment in this stage and better mitochondrial and immunological recovery after drug reduction.


CONCLUSIONS
Administration of high ddl doses together with TDF was associated with mitochondrial damage, which may explain the observed CD4+ T-cell decay. A reduction of the ddl dose led to mitochondrial DNA recovery, but was not sufficient to recover baseline CD4+ T-cell counts. Other mitochondrial toxicity in addition to DNA gamma-polymerase inhibition could be responsible for CD4+ T-cell toxicity.
Negredo
Eugènia
E
Germans Trias i Pujol University Hospital, Lluita contra la Sida and Irsicaixa Foundations, University of Barcelona, 08916 Badalona, Barcelona, Spain. enegredo@flsida.org
Garrabou
Glòria
G
Puig
Jordi
J
Lòpez
Sònia
S
Morén
Constanza
C
Bellido
Rocio
R
Ayen
Rafaela
R
Cardellach
Francesc
F
Miró
Oscar
O
Clotet
Bonaventura
B
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D016049:Didanosine / Q000008:administration & dosage* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D063065:Organophosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000068698:Tenofovir
D019380:Anti-HIV Agents; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000225:Adenine; D016049:Didanosine