July 27, 2005
Several treatment strategies have been designed to deal with patients whose first regimen is failing. Some of the strategies considered include:
Some people believe that the treatment strategy used on patients after their first failure may be influenced by the magnitude of virologic failure at the time that the patient is considered for a change in therapy. Under this belief, if a patient is captured in the early phase of virologic failure, and the provider suspects that no significant mutations have developed, virologic control can be reestablished utilizing a simple treatment regimen.
One such regimen is a quadruple-drug regimen that can now be delivered simply in the form of two drugs: zidovudine/lamivudine/abacavir (AZT/3TC/ABC, Trizivir) + tenofovir (TDF, Viread). It is this combination that is considered a potential option for patients with early virologic failure.
This single-arm study, sponsored by GlaxoSmithKline and presented by Dr. Allan Rodriguez from the University of Miami, looked at the use of the combination of zidovudine/lamivudine/abacavir + tenofovir for the treatment of patients failing their first regimen, with a baseline HIV RNA between 400-10,000 copies/mL at the time of study enrollment.
Patients in this study were required to be failing an initial regimen composed of zidovudine (AZT, Retrovir) or stavudine (d4T, Zerit) plus lamivudine (3TC, Epivir) and either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). A genotypic analysis was also done at baseline. Patients were required to have no more than 2 nuceloside/tide reverse transcriptase inhibitor mutations and no K65R mutation.
Of the 51 patients enrolled in this study, 40 were male and 20 were white. At baseline, trial participants' median CD4+ cell count was 436 cells/mm3 and the median log HIV RNA was 3.3 (1.77-4.88), or 1,972 copies/mL. At baseline, more than 80% of the patients had the M184V mutation and 20% had 1-2 TAMs (M41L, D67N, K70R, L210W, T215Y/F and K219Q/E).
A quarter of the patients discontinued the study on or before week 48 due to adverse events. Of course, this significantly affected the intent-to-treat (ITT) analysis. None of these discontinuations were due to hypersensitivity reaction.
In an ITT analysis (missing = failure), 67% reached an HIV-1 RNA below 400, with 59% below 50 copies/mL. In the as-treated population, the proportion of patients with HIV-1 RNA below 400 and below 50 copies/mL were 87% and 77%, respectively. The median increase in CD4+ cell count from baseline was 71 cells.
Although the results of this study may appear suboptimal, we have to consider that the efficacy endpoint results were driven by the high rate of discontinuations. In fact, only 2 patients met the definition of virologic failure at week 48, which is pretty good. In both these patients, a careful adherence evaluation revealed gross nonadherence in both patients.
Adherence in this study was measured by an adherence survey collected at different time points and by MEMS caps. Perfect adherence was reported in 85% of the patients who completed the study. For this study, perfect adherence was defined as a patient not missing any pills in the 3 days prior to a clinic visit or during the prior weekend to the clinic visit.
This study was initially statistically designed to enroll 100 patients, but because of difficulties with patient enrollment, the study was conducted with only half of the planned population. Nevertheless, considering the simplicity of this regimen, this study makes a compelling argument for the consideration of a quadruple nucleoside/nucleotide regimen for patients experiencing early virologic failure on a thymidine analogue-containing PI- or NNRTI-based (tenofovir-naive) regimen.
Multiple studies have looked at the use of dual antiretroviral class for second-line regimens and demonstrated excellent results. But for patients in whom this option may not be feasible, it is reassuring to see that the simple, easy-to-adhere-to combination of zidovudine/lamivudine/abacavir + tenofovir may remain a viable option to rescue patients experiencing early virologic failure.
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