Partial Immunological and Mitochondrial Recovery after Reducing Didanosine doses in Patients on Didanosine and Tenofovir-Based Regimens

Abstract

Background

Tenofovir disoproxil fumarate (TDF) has a safe toxicity profile; however, administration together with didanosine (ddI) increases ddI levels causing mitochondrial damage and CD4⁺ T-cell decline. We assessed whether a simple reduction of the ddI dose in patients receiving ddI (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 ddI (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 β-actin or COX-IV expression) by western blot.

Results

Treatment with TDF, ddI (400 mg/day) and NVP for 14 months produced significant decreases in mitochondrial parameters and CD4⁺ T-cell counts. The reduction in ddI 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 ddI dose period showed greater mitochondrial impairment in this stage and better mitochondrial and immunological recovery after drug reduction.

Conclusions

Administration of high ddI doses together with TDF was associated with mitochondrial damage, which may explain the observed CD4⁺ T-cell decay. A reduction of the ddI dose led to mitochondrial DNA recovery, but was not sufficient to recover baseline CD4⁺ T-cell counts. Other mitochondrial toxicity in addition to DNA γ-polymerase inhibition could be responsible for CD4⁺ T-cell toxicity.