July 14, 2003
In the past two years, one of the more important clinical trials has been a study called 903, done by Gilead. (For previous coverage of this study, click here.) This study compared what was one of the most successful combinations in terms of the percentage of patients who achieved viral suppression -- d4T (stavudine, Zerit) + 3TC (lamivudine, Epivir) + efavirenz (EFV, Sustiva) -- to a combination of tenofovir (TDF, Viread) with the same 3TC and efavirenz background.
Results have shown overlapping response rates which have been among the highest of any study (about 75 percent by intent to treat showing viral suppression to less than 50 copies/mL, 93 percent for those still on treatment at week 96, and only 1 percent dropping out for adverse effects by week 96). These results clearly demonstrate the importance of defining combinations that are simple and well tolerated as being self-evident but essential in creating such high response rates. Further, the tenofovir arm has been influential in establishing an attractive outcome not just for response rates, but for safety as well, since that arm had few side effects and a notably low rate of lipodystrophy, as seen at week 96. These two posters updated us on this pivotal clinical trial.
Poster 553 reviewed the outcomes of resistance for those on these two combinations at week 96. Both arms had a 12 percent rate of viral "failure" at week 96, defined as a viral load more than 400 copies/mL. Both arms showed similar outcomes on several patterns of resistance. About 5 percent had viral rebound with no resistance mutations, and of those who did have mutations observed, almost all had resistance to efavirenz noted, either by itself or in combination with mutations to the other agents used. The mutation conferring resistance to tenofovir -- K65R -- was seen in eight people (3 percent) in the tenofovir arm, and in two people in the d4T arm, a difference of borderline statistical significance. Since about half of the K65R mutations occurred with a mutation to 3TC as well, the poster reviewed the cross resistance which is seen with these patterns. By the Virco resistance test, the presence of K65R alone shows cross resistance to only 3TC, while the combination of both mutations leads to a predicted resistance of some degree to didanosine (ddI, Videx) and abacavir (ABC, Ziagen) as well. Almost all of those who developed the K65R mutation were successful on a PI-based combination in follow up.
The poster also reviewed baseline predictors of viral failure and noted that the main predictors were a viral load over 5 log (100,000) and a much lower baseline CD4 count (below 130 at baseline versus 253 for the entire study group). Further, they noted that most patients with failure in the study never achieved a viral load less than 50 copies/mL on the regimen. Exploring this further, poster 559 focused on issues of subgroups and predictors of viral suppression. No difference was noted between the outcomes of d4T and tenofovir in the percent of patients achieving a viral load less than 50 copies/mL at week 96 based on gender, ethnicity and baseline viral load more than 5 log as well as a low baseline CD4 count.
These results are reassuring on the issues of how to use these regimens successfully. Since resistance to either regimen is worth preventing, these data do give some guidance on predicting who will not fully achieve viral suppression. While adherence to the regimen often explains a lack of suppression, the results of this study did not find a lack of adherence to be the issue here as most of the people on the study reported high rates of adherence to these simple regimens.
Instead, the researchers found that a low baseline CD4 count plus a viral load over 5 log are important and useful predictors of viral failure. While, overall, the two regimens did equally well at suppressing virus regardless of viral load and CD4 count, there is, for most regimens, a somewhat lower rate of establishing control for patients at the extremes on these values -- and that is confirmed here. Further, the researchers noted that almost all of the patients with failure never achieved a viral load less than 50 copies/mL on the regimen. These results allow us to understand that this regimen is frequently successful. It also, perhaps, challenges us to try to increase the viral suppression rate by targeting patients with these challenging baseline values, and consider options that could either increase the potency of the combination further and/or monitor carefully to ensure patients achieve viral suppression after starting these regimens in order to prevent viral rebound and resistance.
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