Conserved T cell and natural killer cell function in treatment-experienced adults receiving tenofovir plus didanosine as nucleoside reverse transcription inhibitor backbone

Abstract

Summary Anti-retroviral treatment (ART) usually results in efficient control of virus replication and in immune reconstitution. Among potential adverse effects, impairment of immune responses in terms of CD4+ T cell counts has been attributed to some ART regimens, as with didanosine-tenofovir. We studied the functional integrity of adaptive and innate immunity during didanosinetenofovir-containing ART. Two groups of extensively pretreated patients completing at least 48 weeks of ART containing either lamivudine-didanosine (n = 21) or tenofovir-didanosine (n = 25) were identified. In addition to standard clinical immune and virological parameters, we performed a flow cytometric analysis of natural killer (NK) cells, of memory and naive CD4+ T cells and of T cell receptor ab + T cells co-expressing inhibitory NK receptors. Functional analysis consisted in specific and total interferon-g production by NK cells and of recall antigen proliferation of peripheral blood mononuclear cells. Comparable clinical immunological reconstitution and virological control were confirmed in the two groups of patients in the absence of clinically relevant adverse effects. The proportion of CD4+ CD45RA + T cells and of functionally inhibited killer immunoglobulin-like receptor T cell receptor ab + cells, the proliferation to recall antigens as well as NK cell phenotype and function as determined by interferon-g production in patients treated with tenofovir-didanosine were comparable to those treated with a different regimen. Thus, no differences in functional innate or adaptive immune reconstitution are detected in drug-experienced human immunodeficiency virusinfected patients on tenofovir-didanosine nucleoside reverse transcription inhibitor regimens.

Intracellular Nucleotide Levels during Coadministration of Tenofovir Disoproxil Fumarate and Didanosine in HIV-1-Infected Patients

“…The mechanism for these findings appears to be ddI-related mitochondrial toxicity compounded by increased intracellular concentrations of the active triphosphate analog ddATP (9,26,31,43). Consistent with this hypothesis, the incidence of adverse events has been observed to be decreased with ddI dose reduction (3,8,23,41,45).…”

“…The mechanism for these findings appears to be ddI-related mitochondrial toxicity compounded by increased intracellular concentrations of the active triphosphate analog ddATP (9,26,31,43). Consistent with this hypothesis, the incidence of adverse events has been observed to be decreased with ddI dose reduction (3,8,23,41,45).Some recent results have raised questions regarding the efficacy of regimens containing TDF-ddI. Triple-NRTI-only regimens including TDF-ddI in combination with either abacavir (ABC) or lamivudine (3TC) were found to have high rates of treatment nonresponse, virologic failure, and selection of the K65R resistance mutation (12,21,44).…”