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Background:  ART combining tenofovir (TDF) and didanosine (ddI) at a dose of 400 mg per day was recently reported to result in a poor immunologic response with a striking CD4 cell decline despite undetectable HIV RNA. Pharmacologic interaction leading to increased ddI exposure has led to the recommendation that the ddI be adjusted to 250 mg daily when combined with TDF. We hypothesized that ddI at a dose of 250 mg per day may also result in a poor immunologic response when combined with TDF.

Methods: In this retrospective SHCS-analysis of patients treated between October 2001 and June 2004, we identified 416 patients treated with TDF and 219 patients treated with TDF+ddI, respectively. Of the latter, 136 received an adjusted daily dose of 250 mg ddI, 58 underwent dose adjustment (400 ≥ 250 mg) and 25 received a daily dose of 400 mg. Univariable and multivariable linear regression analyses were performed to identify co-factors of CD4 slope such as: dose of ddI, CD4 at baseline, HIV RNA at baseline and over time, gender, age, weight, and presumed mode of HIV acquisition.

Results:  Median CD4 cell count and HIV RNA at the start of TDF differed significantly between patients treated with TDF vs TDF+ddI (CD4, 333 vs 290 cells/μL, p = 0.002; HIV RNA, 70 vs 979 copies/mL, p = 0.0008). In fully adjusted multivariable analysis the CD4 cell slopes were comparable between patients treated with TDF+ddI at 250 mg per day vs TDF without ddI (slope difference 13 cells/μL and year [95% CI –26 to 52]) whereas patients with TDF+ddI at 400 mg experienced a significant loss of CD4 cells (–138 [–215 to –60] p = 0.001). This overall effect on CD4 cells was mainly driven by patients with persistently detectable HIV RNA (–161 [–259 to –62], p = 0.001) while in the small subset of patients with persistently undetectable HIV RNA, CD4 cell slopes did not differ significantly (p = 0.32) irrespective of the ddI dose  (ddI 250 vs 400 mg daily, n = 39 vs n = 5).

Conclusions:  In contrast to our hypothesis, the CD4 cell slope was comparable between regimens containing TDF without ddI and regimens with TDF and an adjusted ddI-dose of 250 mg daily. A poor immunologic response was exclusively found in patients with continuously detectable HIV RNA, treated with ddI at 400 mg daily combined with TDF. These results suggest that treatment with TDF and ddI does not lead to an increased risk of a poor immunologic response if the ddI dose is adjusted to 250 mg per day.

Keywords: didanosine; tenofovir; toxicity