July 13, 2004
Last year's 2nd IAS Conference in Paris will be remembered in part for the series of presentations showing the early failure of regimens containing the triple-nucleoside combination of lamivudine (3TC, Epivir), abacavir (ABC, Ziagen) and tenofovir (TDF, Viread). As researchers reviewed the consistent and disappointing findings of these studies, their questions turned to why this failure was occurring. A few possibilities were cited, including the risk that there may be some unknown intracellular interactions between these drugs, specifically between tenofovir and abacavir (the other possible nucleoside drug interactions have been previously studied, with reassuring results). With that question in mind, Dr. Hawkins and colleagues completed the research needed to find the answer.
Their study enrolled 15 HIV-infected people who were taking a regimen containing tenofovir and abacavir. In the cell, these drugs undergo a chemical change that turns the ingested forms into ones that are active against HIV. This study measured the more active form of these chemicals in cells, not simply the amount that exists in the blood, to see if there was any unexpected "antagonism" between drugs within cells. This antagonism, if present, could lower the target levels needed for 1 or both of these drugs to be fully active against HIV.
The authors initially measured levels of both drugs in patients taking a combination of the two. For the next 28 days, they monitored tenofovir levels in those randomly assigned to stop abacavir, and abacavir levels in those assigned to stop tenofovir. Of note, other drugs were substituted to prevent the rebound of HIV when the study drugs were stopped.
The results were very clear. When the 2 drugs were given together, there were no changes compared to baseline in the levels of either drug when the other 1 was stopped. In other words, tenofovir levels were stable whether or not abacavir was present, and vice versa. This stability was maintained for the entire 28-day period.
In the second part of the study, the drug that was initially continued was stopped, in part to document how the cellular levels of the drugs would drop if there was antagonism within cells. The authors observed slow, continuous drops in the levels of each drug over the next few days. Abacavir levels fell with a "half-life" of 12-19 hours, while tenofovir remained in the body longer, with a half-life of 60 hours.
These results are quite reassuring to the field. The lack of interaction between the drugs means that they can safely be used together in more successful combinations that do not rely on the triple-nucleoside approaches of last year. The study also adds data to an ever more interesting discussion in the field of HIV treatment about the differences in the half-lives of drugs. Finally, the findings show that there may be differences between drugs that allow them to work well once daily, but can also provide a "cushion" for people who miss an occasional dose in such regimens.