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Dose-dependent influence of didanosine on immune recovery in HIV-infected patients treated with tenofovir

Karrer, Ursa; Ledergerber, Brunoa; Furrer, Hansjakobb; Elzi, Luigiac; Battegay, Manuelc; Cavassini, Matthiasd; Gayet-Ageron, Angèlee; Hirschel, Bernarde; Schmid, Patrickf; Russotti, Marinag; Weber, Rainera; Speck, Roberto Fa; the Swiss HIV Cohort Study

Clinical Science

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.

Design and 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/μl 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/μl 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.

From the aDivision of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich

bDivisions of Infectious Diseases, University Hospitals of Bern

cBasel

dLausanne

eGeneva

fDivisions of Infectious Diseases, Cantonal Hospitals of St. Gallen

gLugano, Switzerland.

* See Appendix.

Received 22 March, 2005

Revised 26 July, 2005

Accepted 8 August, 2005

Correspondence to U. Karrer, MD, Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. E-mail: urs.karrer@usz.ch

These data were partially presented at the XII Conference on Retroviruses and Opportunistic Infections in February 2005 in Boston, MA, Abstract no. 588.

© 2005 Lippincott Williams & Wilkins, Inc.