Paradoxical CD4 response with tenofovir and ddI backbone
Simon Collins, HIV i-Base
Several studies have previously reported a caution for toxicity or blunted immune responses in some patients using tenofovir and ddI together. A database analysis from Madrid, provided an indication for the likely mechanism, even though the results from the study were still too early to give an indication of risk in patients using tenofovir with dose-adjusted ddI
Barrios and colleagues from Hospital Carlos III, Madrid, presented an analysis of PI-sparing combinations including 100 patients who were using both tenofovir and ddI in their combination, compared to a similar number of patients using either drug separately or using neither drug. 
Some of the smaller studies that have already suggested a caution to using tenofovir and ddI together as a nucleoside combination were highlighted as background at the beginning of the presentation. [2, 3, 4]
As well as analysis by nucleoside, the study looked separately at response in treatment naïve patients and experienced patients switching to a simplified combination.
In treatment naïve patients CD4 response showed increases of +148 cells/mm3 over the first six months followed by a trend to drop back just below baseline of around 300 cells/mm3 by month 12. While this showed statistical significance (p<0.05 compared to baseline) patient numbers at 0, 6 and 12 months were 18, 17 and 10 respectively.
Patients switching to NNRTI simplification regimens with tenofovir/ddI showed an increase of +29 cells/mm3 which returned to baseline of around 570 cells/mm3 by month 12, with patient numbers being 263, 187 and 175 at the same time points. Of this group, 78 (45%), 54 (31%) and 25 (14%) patients lost >50, >100 and >200 cells/mm3 respectively. Patients were virologically suppressed prior to, and after the simplification switch.
Many of these patients did not dose reduce ddI (from 400/250mg to 250/200mg, depending on weight) after the interaction with tenofovir discovered. When the analysis looked at patient using reduced vs high dose ddI, the concern for naïve patients and the significance in decline in the switch patients was no longer significant.
Time on high dose ddI and weight were both statistically significant variables associated with CD4 decline in the multivariate analysis (p= 0.002 and p<0.001 respectively). Levels of plasma ddI at Cmin were neither predictive, nor significantly different between reduced and high dose ddI arms, but perhaps AUC and Cmax would have been more appropriate parameters to investigate.
As would be expected now, ddI/tenofovir with a third nucleoside performed particularly poorly, but again this is clearly no longer recommended practice.
Although reduced-dose ddI is now standard practice, and these triple nucleoside regimens are not used, the caution for paradoxical CD4 responses in virologically controlled patients using ddI/tenofovir were still reported in this study in significant number to warrant caution.
The hypothesis to explain these results was suggest that as both tenofovir and ddI are adenosine analogs, a synergistic effect of their metabolites could enhance mitochondrial damage, compromising energy output in CD4 cells, or by creating a cytostatic imbalance in the physiologic adenosine pool, impairing the turnover of CD4 cells.
The largest CD4 declines or most concern certainly appear driven by not using the recommended dose reduction of ddI to 250mg (200mg if weight <60kgs). This was well publicised and followed in the UK, when the PK interaction was first realised (see HTB Vol 3 No 9, Nov 2002 and Vol 4 No 1, Jan 2003).
This doesn’t explain lower level CD4 declines seen in this study and reported elsewhere. Although the initial PK interaction of these QD drugs that lifts the requirement to take ddI on an empty stomach increase convenience, the choice of an alternative partner nucleoside for either drug would appear appropriate in patients who fail to achieve satisfactory CD4 responses.
- Paradoxical CD4+ T-cell decline in patients with complete virus suppression under tenofovir plus didanosine combination. 41st ICAAC, Washington, 2004. Abstract H-1132.
- Martinez et al. Pancreatitis Lancet 2004; 364:65.
- Garcia-Benayas et al – hyperglycemia; in press.
- Negredo et al. CD4 declines. AIDS 2004; 18:459.