Additional reporting by Michael Carter
The combination of tenofovir and ddI may result in unexpected declines in CD4 cell count, according to two Spanish studies presented at recent international conferences, but the phenomenon is not clearcut and needs further investigation, according to other findings presented to the Seventh International Congress on Drug Therapy in HIV Infection this week in Glasgow.
A retrospective study presented to ICAAC by Negredo showed that reducing the dose of ddI from 400mg daily to 250mg led to an improvement in CD4 cell count in individuals who experienced a deterioration in their CD4 cell count after taking a HAART regimen including tenofovir and the 400mg daily dose of ddI.
Investigators noted that 51% of patients taking ddI (at 400mg a day) and tenofovir experienced a fall of at least 50 cells/mm3 after a year of HAART including the two drugs, with median CD4 cell counts falling by 169 cells/mm3 (median CD4 cell count at baseline 716 cells/mm3, median CD4 cell count after 48 weeks, 547 cells/mm3, p = 0.017).
After the dose of ddI was reduced, the investigators noted a progressive improvement in CD4 cell count. After 36 weeks of taking the reduced dose of ddI, the median increase in CD4 cell count was 88 cells/mm3. Four of 20 patients experienced CD4 cell recovery to baseline by week 36.
The investigators also reduced the ddI dose to 250mg daily in the patients who had not experienced a fall in their CD4 cell count. By week 36 these patients had experienced a median gain in CD4 cell count of 17 cells/mm3.
A full summary of the data from this study is available as a capsule summary at the Clinical Care Options for HIV website.
Tenofovir and ddI – higher plasma concentrations of ddI have cytostatic effect
Concerned about reports that the use of tenofovir and ddI in HAART regimens caused a fall in CD4 cell count, Barrios studied changes in CD4 cell counts in HIV-positive individuals taking the two drugs as part of their HIV therapy. Their analysis included 64 treatment-naïve individuals, 195 patients who were simplifying their HAART regimen, and 43 patients who were changing their HIV treatment because of failure.
Investigators noted that simplification patients taking tenofovir and ddI experienced a significant decline in their CD4 cell count, which was not seen amongst patients who simplified to other regimens. However numbers in each group analysed are small, the investigators admit, and should be treated with caution.
Individuals taking a nucleoside analogue as their third drug along with tenofovir and ddI experienced a marked fall in their CD4 cell count compared to patients taking the two study medications with a non-nucleoside (NNRTI) (tenofovir and dual NRTI patients had a median fall in CD4 cell count after twelve weeks of 385 cells/mm3 versus a fall of 66 cells/mm3 in patients taking an NNRTI, p
Declines in CD4 cell count appeared to be associated with plasma concentrations of ddI. The investigators noted that patients taking a 400mg daily dose of ddI experienced greater falls in their CD4 cell count than patients prescribed the 250mg daily dose of the drug (p
The investigators emphasise that these falls in CD4 cell count occurred despite virologic failure. They suggest that tenofovir and ddI are metabolised in a similar way, producing higher plasma concentrations of ddI, which have a cytostatic effect.
A full summary of the data from this study is available at the Clinical Care Options website.
Tenofovir/ddI in the TORO study – less clearcut effects
In a third study of participants in the TORO 1 and 2 studies of T-20, 48 week data on patients who received ddI and tenofovir in their salvage regimen were compared with those of patients who received other drug combinations in their background regimen. Approximately 85% of patients who received tenofovir/ddI in the study received a 400mg ddI dose.
Amongst patients who received T-20, those who received ddI with tenofovir (n=72) were significantly more likely to experience a lower CD4 cell increase after starting treatment than patients who received ddI without tenofovir (n=257) (p=0.045), but the difference in CD4 cell count recovery was not significant when compared with patients who received tenofovir alone (n=104) or nucleosides other than ddI and tenofovir (n=228).
However, when the researchers looked at CD4 responses in patients with viral load below 400 copies at week 48 (those who might be expected to have the best CD4 cell response to treatment), there was no significant difference in responses between the treatment groups, although the number of ddI/tenofovir treated patients was small (n=21).
Potential mechanism
According to Professor David Back of Liverpool University, the potential mechanism causing CD4 cell depletion or impaired CD4 cell recovery is tenofovir’s inhibitory effect on purine nucleoside phophorlyase, which catalyses the breakdown of purines, including ddI. This leads to increased intracellular concentrations of the drug. He cited a study showing that inhibition of this enzyme can cause increases in the intracellular concentrations of dATP and dGTP in T-cells, leading to apoptosis.
Further research
Further research drawing on other large studies of salvage treatment such as RESIST-1 & 2 and BMS 045, as well as comparisons from large cohorts of treatment-experienced patients, would be useful before jumping to conclusions. In particular, more evidence is needed on the effects of the lower ddI dose (250mg) that began to be adopted in early 2003 after the TORO study had been completed.
Barrios A et al. Paradoxical CD4 T-cell decline in patients with complete virus suppression under tenofovir plus didanosine combinations. 44th ICAAC, Washington, abstract H-1132, 2004.
Negredo E et al. CD4 cell count changes after reduction of didanosine dosage in patients receiving standard doses of didanosine and tenofovir-based regimens. 44th ICAAC, Washington, abstract H-561, 2004.
Negredo E et al. Concurrent administration of tenofovir (TDF) and didanosine (ddI) compromises immunologic recovery in treatment-experienced patients. Results from the TORO studies. Seventh International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P3, 2004.