ddI may retain activity in nucleoside experienced patients

A randomised study compared addition of either ddI (n=110) or placebo (n=68) for four weeks to current therapy of treatment experienced patients with detectable viral loads over 1,000 copies/mL. The primary endpoint was change in viral load between baseline and week 4. Resistance was analysed by genotype at baseline and week 4.

Median baseline viral load and CD4 count were 3.8 log copies/ML and 378 cells/mm3 respectively. Patients had a median of three thymidine analogue mutations and four nucleoside analogue mutations. Ranges were not provided for any of these baseline parameters.

Viral response correlated closely with the extent of baseline resistance, with an approximate 0.6 log drop still reported with a median of four nucleoside-associated mutations (NAMs) and three thymidine-associated mutations. Tolerability was similar in each group.

Comment

Without more detailed presentation of treatment histories of these patients it is unclear whether this short-term viral suppression would be sustained. Data was not for example presented on any changes to the resistance profiles between baseline and week four. If introduction of ddI provided selective pressure for the return of archived virus from previous ddI and other nucleoside use, then the benefit is only likely to be limited.

If, however, it confirms antiviral activity with low-level nucleoside resistance, then this could provide an important boost for people who still fall just short of the potency required to reach and sustain and undetectable viral load. This is particularly important when constructing third-line and salvage regimes.

In addition, it is well documented that didanosine has good activity in monocyte/macrophage cell lines. HIV inhibition in these cell lines in vitro requires 100-fold lower drug levels than is required to suppress replication in lymphoblastic cells. Perhaps sensitivity to didanosine is selectively retained in these cell lines even in the presence of NAMs, giving additional benefit in nucleoside-experienced patients.

Molina JM, Marcellin AG, Pavie J. Didanosine (ddI) in treatment-experienced patients: Results from a randomised double-blind placebo controlled study (A1454-176 – JAGUAR). 43rd ICAAC, September, 2003; Abstract H-447.