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Viral Failure to Tenofovir/Abacavir/3TC
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Reported by Jules Levin
This study and the problems highlighted by this study were discussed at the IAS Conference in July in Paris. But this was the first time the results of this study have been formally presented.
"Early Non-Response to Tenofovir + Abacavir and 3TC in a Randomized Trial Compared to Efavirenz + Abacavir and 3TC: ESS30009 Unplanned Interim Analysis"
This study was stopped early due to a high viral failure rate in patients taking the combination of 3TC-Abacavir-Tenofovir. A similar finding was reported in a study at IAS by Charles Farthing at AIDS Healthcare Foundation in LA. As a result it is recommended that this 3-drug combination not be used alone. Further studies are ongoing to analyze the reasons why this combination led to a high viral failure rate.
Joel Gallant reported the study results in a late breaker oral presentation yesterday at ICAAC (H-1722a). 200 patients were randomized to either efavirenz-abacavir-3TC or tenofovir-abacavir-3TC. The purpose of the study was to explore the potential benefits of the TDF/ABC/3TC regimen, which could be a once a day regimen simplified regimen. Once daily 3TC was approved by the FDA and GSK is planning a fixed dose combination of abacavir/3TC. At this conference study results were reported finding that abacavir once daily had comparable viral load suppression when compared to abacavir twice daily. In the study patients also received 3TC plus efavirenz. About 50% of the study patients were white and 50% black and hispanic. Median viral load was 58,000 copies/ml. Median CD4 count was 250-280. The study was intended for 48 weeks with an enrollment of 360 patients.
Gallant reported that following rapid study enrollment, several cases of early virologic non-response in the TDF plus abacavir/3TC arm were reported to GlaxoSmithKline. An urgent unplanned interim analysis was performed for study patients with >8 weeks HIV viral load data (n=194 of the 354 randomized patients). Virologic non-response was defined as: (1) <2 log decline in HIV RNA by week 8, (2) >1 log rebound from nadir (lowest viral load achieved on study treatment) at any subsequent visit, or (3) confirmed HIV RNA >400 copies/ml following two consecutive HIV RNA values <50 copies/ml.
VIROLOGIC NON-RESPONSE
For patients with at least 8 weeks viral load data 95% receiving EFV/ABC/3TC had <50 copies/ml compared to 29% for patients receiving TDF/ABC/3TC.
For patients with virologic non-response to TDF/ABC/3TC (n=36), 64% had the double drug mutation of K65R and M184V (n=23). K65R is associated with TDF resistance and M184V is associated with 3TC resistance. 13 patients (36%) had the M184V mutation alone.
Several hypothesis have been proposed to explain this phenomena
--inadequate efficacy with once daily ABC/3TC. Gallant said this is unlikely given the response of the EFV arm.
--drug interaction between TDF and ABC. Gallant reported that a pilot PK study reported at ICAAC (n=8) showed no TDF effect on single-dose plasma ABC (Kearney et al, abst. A-1615).
--intracellular pharmacologic interaction. Gallant said intracellular TDF assay is not available but this is under investigation.
--low genetic resistance barrier to TDF+ABC/3TC. Gallant said, and this is a popular explanation, selection and outgrowth of minority population of pre-existing mutants may explain rapid failure and rebound. This is currently under investigation.
Gallant concluded:
--TDF/ABC/3TC should not be used as a triple combination regimen
--a large proportion of patients with non-response to TDF/ABC/3TC had K65R and M184V
--implications for regimens containing TDF/ABC/3TC with a 4th drug (eg, AZT, PI, NNRTI) are unclear. Clinical trials are in progress
--EFV/ABC/3TC is a promising two-pill, once daily regimen; long-term data are forthcoming.
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