SAN FRANCISCO (Reuters Health) Feb 09 - In efforts to increase patient compliance and improve quality of life, much recent attention has focused on simplifying antiretroviral regimens. However, a series of reports presented at the 11th Annual Retrovirus Conference this week suggest that these regimens can be simplified too far, resulting in rapid treatment failure accompanied by the emergence of drug-resistant mutations.
"You can oversimplify regimens," noted Dr. John Mellors, of the University of Pittsburgh, at a press briefing. Of particular concern is the emergence of the 65R reverse transcriptase mutation related to the omission of AZT from antiretroviral treatment regimens, he said. Some of these regimens offer an "easy escape route" for AZT involving the 65R and the 184V mutation.
Specifically, certain antiretroviral combinations that include tenofovir, lamivudine (3TC), didanosine or abacavir appear to not be potent enough to suppress viral replication and offer HIV-1 a "low genetic barrier" for resistance through the reverse transcriptase mutations 65R and 184V.
To investigate the trends in the prevalence of 65R, Dr. Mellors and colleagues searched databases for the frequency of 65R and its association with other nucleoside reverse transcriptase inhibitor mutations.
Out of 60,000 samples that contained any NRTI mutations, Dr. Mellors' group found that 65R frequency increased from 0.8% in 1998 to 3.8% in 2003. In addition, they found that 65R is a multi-NRTI resistance mutation that reduces "susceptibility to all D-, L-, and acyclic NRTI tested except those containing a 3'-azido moiety."
The increased prevalence of the "previously rare" 65R mutation appears to be due to the use of nucleoside combinations that lack AZT.
In another study, Dr. R. Elion of the George Washington School of Medicine in Washington, DC and colleagues report a poor virologic response and the rapid emergence of drug resistance among 88 antiretroviral nave patients receiving once-daily Trizivir and tenofovir. Trizivir combines three antiretroviral drugs--AZT, 3TC and abacavir.
The findings of a third study, presented by Dr. J. Jemsek of Huntersville, North Carolina, involved patients who received once-daily treatment with a triple nucleoside regimen containing didanosine, 3TC and tenofovir. This regimen also led to a high frequency of poor virologic response and the early emergence of drug resistance.
Last year, an unexpected high rate of virologic failure resulted in the termination of the portion of a phase III trial in which HIV-infected patients were receiving a fixed-dose co-formulation of abacavir and 3TC (Epivir) in combination with tenofovir once daily. About half of these patients experienced virologic failure at week 8 (see Reuters Health report from September 22, 2003).
Also last year, the AIDS Healthcare Foundation asked U.S. regulators to withdraw approval for GlaxoSmithKline Plc's combination HIV drug Trizivir in light of a study showing it was inferior to other treatment combinations (see Reuters Health report August 19, 2003).
The National Institutes of Health said in March it had halted part of a trial comparing Trizivir alone to other combinations because Trizivir by itself was less effective at suppressing patients' HIV load.
Source: medscape.com
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