December 16, 2005
Adding tenofovir (TDF, Viread) to zidovudine/lamivudine/abacavir (AZT/3TC/ABC, Trizivir) does not appear to improve virologic outcome and does nothing to reduce treatment discontinuation rates in treatment-naive patients, according to a relatively small study by U.S. researchers. When considered alongside other clinical trial results, the findings solidify the undesirability of NRTI-only regimens for first-line therapy.
Regimens consisting only of nucleoside/tide reverse transcriptase inhibitors (NRTIs), such as zidovudine/lamivudine/abacavir or zidovudine/lamivudine (AZT/3TC, Combivir) + tenofovir, have been disappointing due to their relative lack of potency in clinical trials, as well as their low barrier to the development of resistance mutations, such as M184V and/or K65R.
As a result, many clinicians have concluded that there are only specific subsets of patients for whom such regimens would be an option, such as women of childbearing potential and patients receiving rifampin (Rifadin, Rimactane) for the treatment of tuberculosis. Even so, studies continue to explore the potential value of NRTI-only regimens; the COL40263 protocol, led by Cal Cohen of the Community Research Initiative of New England, is one such study.
COL40263 was an open-label, single-arm, 48-week study of 123 treatment-naive patients assigned to receive the quadruple-NRTI combination of zidovudine/lamivudine/abacavir + tenofovir as three pills once a day. The median baseline CD4+ cell count was 222 cells/mm3 and the median HIV plasma viral load was 5.08 log10 copies/mL.
Study discontinuation was quite common: Only 71 (58%) trial participants completed the 48 weeks of the study, with many discontinuations due to adverse events (14, 8 of which were cases of abacavir hypersensitivity), loss to follow-up (13) or virologic failure (12). Twelve of the 14 virologic non-responders had a baseline HIV plasma viral load of more than 5.00 log10 copies/mL, highlighting this regimen's inability to suppress HIV in patients with a high baseline viral load.
In addition, even in patients for whom the regimen could be considered a success, this success was modest at best: In an intent-to-treat (missing = failure) analysis, only 51 patients (41%) achieved a plasma viral load below 50 copies/mL, and only 63 patients (51%) reached a viral load below 400 copies/mL. Among the 67 patients for whom CD4+ cell count data was available at week 48, CD4+ cell count was found to have increased by a median of slightly more than 120 cells/mm3 from baseline.
In addition, there were some beneficial changes in total cholesterol (a drop of 9 mg/dL) and triglycerides (a drop of 3.5 mg/dL), and no deleterious effects on mitochondrial DNA or bone mineral density (in a subset of patients). Finally, DEXA (dual energy X-ray absorptiometry) scans revealed a trend toward an increase in arm fat, leg fat and trunk fat through 48 weeks of therapy, changes that could actually be deleterious and would require careful follow-up.
This study raises a number of concerns. The addition of tenofovir to zidovudine/lamivudine/abacavir does not appear to produce better virologic suppression than has been seen with zidovudine/lamivudine/abacavir alone in studies such as ACTG 5095.1 Virologically, this quadruple-NRTI regimen remains inferior to double-class initial regimens. The large number of discontinuations (42%) over 48 weeks of observation raises additional concerns, as fully half of these were due to loss of follow-up, withdrawal of consent and protocol violations.
The Bottom Line
These results show that a quadruple-NRTI regimen is not a credible, equal alternative to currently recommended highly active antiretroviral therapy regimens, particularly in patients with higher baseline HIV plasma viral load measures. It is not even clear that, in the patients for whom such NRTI-only regimens would most likely be prescribed (e.g., some pregnant women and some individuals receiving rifampin for the treatment of tuberculosis), the use of tenofovir adds anything to zidovudine/lamivudine/abacavir in terms of potency.
In the end, COL40263 helps to confirm what many HIV clinicians have already concluded: Single-class regimens should only be used as initial therapy in exceptional circumstances (for instance, another study presented at this conference suggested a possible use for zidovudine/lamivudine/abacavir + tenofovir in heavily treatment-experienced patients), and their efficacy should be carefully monitored to avoid limiting a patient's future treatment options.
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