Dose-dependent influence of didanosine on immune recovery in HIV-infected patients treated with tenofovir.
BACKGROUND
Antiretroviral therapy (ART) containing tenofovir disoproxil fumarate (TDF) and didanosine (ddI) has been associated with poor immune recovery despite virologic success. This effect might be related to ddI toxicity since ddI exposure is substantially increased by TDF.


OBJECTIVE
To analyze whether immune recovery during ART with TDF and ddI is ddI-dose dependent.


METHODS
A retrospective longitudinal analysis of immune recovery measured by the CD4 T-cell slope in 614 patients treated with ART containing TDF with or without ddI. Patients were stratified according to the tertiles of their weight-adjusted ddI dose: low dose (< 3.3 mg/kg), intermediate dose (3.3-4.1 mg/kg) and high dose (> 4.1 mg/kg). Cofactors modifying the degree of immune recovery after starting TDF-containing ART were identified by univariable and multivariable linear regression analyses.


RESULTS
CD4 T-cell slopes were comparable between patients treated with TDF and a weight-adjusted ddI-dose of < 4.1 mg/kg per day (n = 143) versus TDF-without-ddI (n = 393). In the multivariable model the slopes differed by -13 CD4 T cells/mul per year [95% confidence interval (CI), -42 to 17; P = 0.40]. In contrast, patients treated with TDF and a higher ddI dose (> 4.1 mg/kg per day, n = 78) experienced a significantly impaired immune recovery (-47 CD4 T cells/microl per year; 95% CI, -82 to -12; P = 0.009). The virologic response was comparable between the different treatment groups.


CONCLUSIONS
Immune recovery is impaired, when high doses of ddI (> 4.1 mg/kg) are given in combination with TDF. If the dose of ddI is adjusted to less than 4.1 mg/kg per day, immune recovery is similar to other TDF-containing ART regimen.
Karrer
Urs
U
Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, Switzerland. urs.karrer@usz.ch
Ledergerber
Bruno
B
Furrer
Hansjakob
H
Elzi
Luigia
L
Battegay
Manuel
M
Cavassini
Matthias
M
Gayet-Ageron
Angèle
A
Hirschel
Bernard
B
Schmid
Patrick
P
Russotti
Marina
M
Weber
Rainer
R
Speck
Roberto F
RF
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology; D000328:Adult; D018791:CD4 Lymphocyte Count; D016049:Didanosine / Q000008:administration & dosage* / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage* / Q000276:immunology; D012367:RNA, Viral / Q000032:analysis; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000276:immunology; D000068698:Tenofovir; D016896:Treatment Outcome
D063065:Organophosphonates; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000225:Adenine; D016049:Didanosine