February 25, 2005
The combination of abacavir (ABC, Ziagen) and lamivudine (3TC, Epivir), given once daily (QD) or twice daily (BID), or as a fixed-dose combination (FDC), has been extensively studied in antiretroviral-naive patients as part of non-nucleoside reverse transcriptase inhibitor (NNRTI)- and protease inhibitor (PI)-containing regimens. Multiple clinical studies have proved the efficacy and safety of this combination, including the studies that led to the final approval of abacavir for once-daily use.1,2
It appears clear by now that the use of FDCs simplifies HIV care by reducing pill burden and dosing frequency. Some studies are starting to show some improvement in adherence with the use of FDCs. These improvements in adherence will invariably translate into better virologic outcome, and decreased morbidity from the progression of the HIV disease.
The SEAL study (also known as ESS30008) is a GlaxoSmithKline-sponsored study comparing the use of FDC abacavir/lamivudine (ABC/3TC, Epzicom, Kivexa) QD versus taking both abacavir and lamivudine as separate formulations BID. This phase III, randomized, open-label study enrolled HIV-1-infected patients who initiated treatment with abacavir BID and lamivudine BID, plus a PI or an NNRTI. At the time of study entry, all patients had been on therapy for at least 3 months, and they had an HIV RNA of less than 400 copies and a CD4+ cell count of greater than 50 cells.
Two hundred sixty patients were then randomized to continue their BID abacavir + lamivudine regimen (BID group), or to switch to the QD FDC abacavir/lamivudine (QD group). They all continued their third drug, which for two thirds of the patients was an NNRTI. Because these patients were already on therapy, the rate of discontinuation after switching or continuing with their regimen was very low (8% versus 10%, respectively).
The proportion of patients who continued to respond (non-virologic failures) was 95% for the QD group and 93% for the BID group. These results do not change if the patients are stratified by the third drug (PI or NNRTI) in their regimen. The proportion of patients with an HIV RNA of less than 50 copies was 81% for the QD group and 82% for the BID group in an intent-to-treat analysis. The CD4+ cell counts, which were fairly high at baseline (median 554 cells), remained stable in both groups.
Overall, abacavir and lamivudine, either given as individual components or as a FDC, were very well tolerated. Only 2 subjects discontinued the study due to adverse events, which were felt not to be related to study medication. As expected, no hypersensitivity to abacavir was reported in this experienced population.
During the 48 weeks of the study, 6 patients developed virologic failure: 4 were in the NNRTI group and 2 in the PI group. The virologic failure of these 6 patients was felt to be secondary to non-adherence.
For this study, the optimal adherence was considered anything above 95% based on previous data. The proportion of patients achieving this high level of adherence was 39% in the QD group and 31% in the BID group.
The authors concluded that FDC abacavir/lamivudine is associated with a potent and durable antiviral response, which was non-inferior to the response seen with the use of abacavir + lamivudine when given as separate components BID.
The results of this study, in my opinion, are expected and, not surprisingly, good. Patients already taking a stable antiretroviral regimen, and who have an undetectable viral load, are expected to continue to do well if the regimen is continued, or if the regimen is changed to something that appears to be simpler to take. Most patients who discontinue a study due to tolerability or adverse events do so at the beginning of their therapy. Because these patients were already taking abacavir and lamivudine, it was expected that few would have either tolerability or safety issues.
There are 3 important take-home messages from this study:
At this point, there may be no good reason for a patient who can benefit from a QD regimen to continue to take abacavir + lamivudine BID rather than the new FDC abacavir/lamivudine.