July 12, 2002
This study was among the most discussed by at least some participants at the meeting in Barcelona in part because of the impressive overall success of the study -- representing perhaps another benchmark in terms of how well we can establish viral suppression in those just starting their first antiretroviral regimen.
The study design was to compare one of the more successful combinations noted to date -- Sustiva (efavirenz) and Epivir (3TC or lamivudine) were included in both arms of the regimen. The study compared using either Zerit (d4T, stavudine) or Viread (tenofovir) as the third drug in the regimen. The choice of Zerit was made for several reasons, including data from several studies in the past showing that the combination of 3TC and Sustiva with most any third drug did very well, even at high viral loads and low initial CD4+ counts, and when these were combined with d4T, the success rates reported were very high, with a very low rate of initial gastrointestinal upset making it an attractive combination for patients getting started on therapy. Overall, the success rates of both arms were essentially identical for the number/percent of those who achieved viral suppression.
The baseline characteristics were notable because about 25 percent of the 600 people enrolled in this study were women. The average viral load was about 80,000, with a CD4+ count of about 280. Over the first year, only 1 percent of participants dropped off the study due to adverse events, a tribute to the success of both combinations. At the end of week 48, 87 percent of those in both arms had a viral load of less than 400 copies, and when they excluded those who did not have data at week 48, about 95 percent of those on both combinations had a viral load of less than 400 copies. Using the more rigorous 50 copy cutoff, about 82 percent had reached this degree of suppression when including all of those who enrolled, and while not presented, it is reasonable to estimate that about 90 percent had a viral load of less than 50 copies who had continued on the study for the entire time. Both groups had a similar increase in CD4+ count by about 170 cells. There was no difference in the success rates of these combinations for those who entered with a viral load above 100,000 copies, and similar success was noted for those with a pretreatment CD4+ count below 200/mm3.
In terms of safety, both arms did well. There were about 7 percent who had peripheral neuropathy of any severity by week 48 on the d4T arm, while only 2 percent had this occur while on tenofovir. There was a suggestion also of a difference in lipodystrophy (4 percent d4T vs. 1 percent tenofovir) but this was not further described. There also was a difference in the blood lipids with higher values in both cholesterol (53 mg/dL vs. 25 mg/dL) and triglycerides (74 mg/dL vs. 0 mg/dL) for those on d4T compared to tenofovir respectively. There was no difference noted in kidney function, a concern for the class of drugs of which tenofovir is an example nor was there any significant difference yet in serum phosphorus, another concern for these types of agents from prior studies.
This study clearly establishes the role for tenofovir as a component of an initial treatment combination. The high level of success noted for both arms of this study also gives renewed confidence that our current regimens are amply potent, simple, and safe for the vast majority who take them. The suggestion of some potential safety advantages of tenofovir over d4T in terms of blood lipid differences will no doubt be the focus of future presentations of these data. While some physicians may prefer to await longer term data on any new medication to establish its multiyear safety track record, there is no information from other earlier studies to suggest a concern with the ongoing safety of tenofovir after a few years of use. Thus, it is likely this study will lead to the inclusion of the pairing of 3TC/tenofovir as an alternative nucleoside pairing in an initial combination. Of note, as with ddI/3TC, this combination has the advantage of both agents being one pill each, taken just once a day (although this study did not test the regimen in a once a day strategy, as the approval of the use of 3TC as a once daily agent occurred after this study was complete). With the recent availability of a 600 mg Sustiva tablet, the number of simple initial regimens that are very successful has just been expanded by a new arrival.