Trizivir-only arm closed in PI-sparing, naïve therapy trial
1 April 2003. Related: Antiretrovirals, Other news.
Simon Collins, HIV i-Base
Important interim results from a Phase III, randomised, double-blind comparison of three protease-inhibitor-sparing regimens for the initial treatment of HIV infection (AACTG Protocol A5095).
A large randomised US trial (ACTG 5095) comparing triple nucleoside therapy AZT/3TC/abacavir (Trizivir) to two efavirenz containing regimens in almost 1,150 treatment naïve patients has closed the triple-nucleoside arm on the recommendation of the studies data and safety monitoring board (DSMB) due to almost double the incidence of virological failures.
The triple-nucleoside AZT/3TC/abacavir (Trizivir) arm was inferior to efavirenz/AZT/3TC and to the four-drug combination of efavirenz/AZT/3TC/abacavir with patients experiencing virologic failure earlier and more frequently. The data met pre-specified guidelines for stopping this one arm of the study based on virologic failure which was defined as plasma HIV RNA level above 200 copies/ml at least four months after starting study treatment.
At baseline, the median CD4+T cell count was 238/mm 3 ,and the median viral load was 78,825 c/mL, with 57% of subjects having HIV-1 RNA<100,000 c/mL and 43% >100,000 c/mL. After an average of 32 weeks on study, a total of 167 study volunteers experienced virologic failure: 21% in the group receiving ABC/3TC/ZDV versus 10% in the other two groups combined. Virologic failure occurred sooner and more often in those receiving ABC/3TC/ZDV alone, regardless of their initial viral load (whether above or below 100,000 copies/mL, p<0.001for both groups). Although data on CD4+ T cell counts were not available at the time of the interim analysis, the DSMB felt that they would not reverse the outcome.
In a post-review analysis the estimated risk of virologic failure (confirmed HIV RNA >200 c/mL) in those receiving ABC/3TC/ZDV with HIV RNA <200 c/mL was about 7% over three months, compared to 3.5% for subjects on the combined EFV-containing arms.
The NIAID letter to healthcare providers states: “Although we are confident of these findings, they have not been presented at a scientific meeting, peer reviewed, or published. These results will be submitted to the upcoming International AIDS Society meeting in Paris (July 2003), and further analyses (eg, CD4+ T cell count and adherence data) will be forthcoming… It is important to consider this interim study finding in the context of published results, particularly those from prior studies that investigated either triple nucleoside regimens or EFV-based regimens. The risk of virologic failure is clearly an important factor in selecting an initial antiretroviral regimen. Other factors such as safety, toxicity, adherence, preservation of future treatment options, access, cost, and other issues also remain important in selecting the optimal first regimen for an individual patient.”
Additional information about the study design and interim analysis are available on the National Library of Medicine Web site at
http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html
and on NIAID’s Division of AIDS Web site at
http://www.niaid.nih.gov/daids/default.htm
Source: National Institute of Allergy and Infectious Diseases (NIAID).
Comment
These finding are of concern due to the fact that higher incidence of failure was reported across a wide range of baseline viral load levels, and not just at the higher levels above 50-100,000 copies/ml for which triple-nucleoside regimens are currently not recommended?
If awareness of the importance of adherence is now more widely appreciated among patients, these findings could more accurately reflect the differences in potency that were often obscured in earlier studies of Trizivir, when triple nucleoside therapy was compared to more complicated protease-based regimens. Also, in order to assure double-blinding of all study drugs, each patient took two pills each morning and five pills each evening, effectively negating the inherent benefits of a low pill burden with Trizivir?
As supported by other GSK studies, Trizivir may still be more cautiously and appropriately used to provide solid, tolerable, potent, pharmacologically forgiving and four-drug combinations with a low pill burden, as in the third arm of this study?