HIV treatment failure is influenced by patient adherence and drug potency, two new studies suggest. They indicate that drug resistance may be less important than previously thought (Journal of the American Medical Association 2000;283:205 and 229).
Dr Diane Descamps (Bichat-Claude Bernard hospital, Paris) and colleagues have examined the mechanisms of virological failure. Following an intensive induction regime of zidovudine, lamivudine and indinavir, patients were assigned to three maintenance groups - continued triple-drug therapy or two-drug therapy with zidovudine and lamivudine, or zidovudine and indinavir. The researchers compared 58 patients who had viral rebound (treatment failure) with 58 control patients who maintained sustained viral suppression. They assessed adherence to treatment regimens and drug resistance.
Dr Descamps reports that virological failure that occurred during the maintenance phase "was not associated with key zidovudine or indinavir resistance mutations". Poor adherence was associated with virological failure in patients taking triple therapy and in some taking the zidovudine and indinavir combination therapy. In the zidovudine-lamivudine combination group, adherence was not a problem and treatment failures occurred late, suggesting a lack of drug potency, the authors report. In the zidovudine and indinavir group, both poor adherence and a lack of potency may have contributed to virological failures, she says.
Dr Descamps comments that the results have practical implications. "Treatment adherence must be thoroughly investigated in virological failure before switching therapy," she says. "When an initial antiretroviral regimen fails, compounds posing adherence problems must be identified and replaced by simpler alternatives."
In the second study, Dr Diane Havlir (University of California, San Diego) and colleagues investigated drug susceptibility after viral rebound in patients receiving regimens containing indinavir. She concludes that their results challenge the previously held view that treatment failure occurring in a regimen containing a protease inhibitor (PI) is a result of resistance. "Suboptimal antiviral potency permits rebound," she says.
These findings have clinical implications, Dr Havlir comments. In a failed regimen, the predominant virus may be resistant to one but not all of the antiviral components (not necessarily the PI). Also, not all drugs in a failed regimen should be considered lost options. She suggests that testing for drug resistance early after a loss of viral suppression may be useful to identify which components could be useful in future regimens.
In an accompanying editorial (Ibid, p250), Dr Martin Markowitz (Aaron Diamond AIDS Research Centre, Rockefeller University, New York) comments: "Taken together, these studies demonstrate that virologic failure is complex and not exclusively mediated by viral resistance." Non- adherence was "clearly a critical factor" but could not be assumed to be the origin of treatment failure, he says.