In order to prevent resistance and maintain antiretroviral activity, clinical investigators have wondered whether if it would be better to alternate therapy rather than maintain patients on a single combination. A group of French investigators designed a study with dual nucleoside reverse transcriptase inhibitors (NRTI) to try to answer this question. In addition, this is the third study presented today that compares two commonly prescribed combinations of nucleosides, and the only one that puts them head-to-head as part of 2-drug combinations.

Three treatments, administered in an open-label fashion, were compared over a 24 week period:

• ZDV + 3TC (Group 1)
• d4T + ddI for 12 weeks followed by ZDV + 3TC for 12 weeks (Group 2) and
• d4T + ddI (Group 3).

Patients were antiretroviral therapy naïve with pre-treatment viral loads between 10,000 and 100,000 copies/mL (bDNA) and CD4+ counts > 200 cells/mm3.

151 patients were enrolled into this study. Baseline viral loads ranged between 25,000 -- 40,000 copies/mL for the three arms, and baseline CD4+ counts were approximately 380 cells/mm3. After 24 weeks of therapy, patients in Group 3 (d4T + ddI) had a mean viral load reduction of 2.2 log and 90% had viral loads < 50 copies/mL compared to a mean viral load reduction of -1.3 log for the patients in Group 1 with 42% < 50 copies/mL, differences that were statistically significant. Patients in Group 2 had viral load reductions that paralleled those of Group 3, until week 20, 8 weeks after the switch from d4T + ddI to ZDV + 3TC. At that point viral loads increased by more than 0.5 log, such that viral loads were reduced by -1.5 log at week 24, and 62% of patients had viral loads < 50 copies/mL.

It appears that switching patients from d4T + ddI to ZDV + 3TC is not a very good idea. Although it is unlikely that practitioners or patients would be considering when these drugs are used in only two drug combinations, the fact that activity was lost when d4T + ddI was switched to ZDV + 3TC suggests that alternating therapy in this manner should not be done, even if the drugs are used with a third agent. As I said, there is little head-to-head data comparing d4T + ddI and ZDV + 3TC as dual therapy. In this study, the nod goes to d4T + ddI. However, as shown by the START II trial, if there are differences in the activity of d4T + ddI and ZDV + 3TC, these differences may be blunted when the drugs are used as part of 3-drug combinations.