Good adherence in patients who are failing a HAART regimen may paradoxically lead to the very thing which good adherence is meant to prevent – high level resistance to protease inhibitors – according to a study conducted by Dr John Walsh of the Chelsea and Westminster Hospital, London.
He examined plasma levels, genotypic and phenotypic resistance to protease inhibitors and adherence behaviour in a group of prospectively recruited patients failing a combination containing either nelfinavir (16) or indinavir (18). Failure was defined as two consecutive viral load measurements above 1,000 copies. A control group of patients taking the same PIs but with three consecutive viral load measurements below 50 copies was also recruited.
Adherence was measured by pill counts, questionnaire and pill bottles with computer chips which counted how many times the bottle had been opened. Plasma drug levels were measured 2, 4 and 6 hours after observed dosing.
There was a strong association between genotypic resistance mutations associated with PI treatment and a high level of adherence (99.2%) in those experiencing viral load rebound. Individuals with poor adherence (average 75.2%) were significantly more likely to have wild type virus or naturally occurring genotypic changes (polymorphisms) than PI-associated mutations.
Plasma drug level drug testing showed a significant association between viral genotypic resistance and a lower nelfinavir trough level. These patients may have poor drug absorption or rapid drug elimination; coupled with good adherence this would be expected to lead to frequently sub-optimal drug levels that would select for drug resistant virus.
On the other hand, in those with poorer adherence, “adherence may be so low as to fail to drive the selection of resistance mutations” said Dr Mark Nelson, presenting the results of the study on behalf of Dr John Walsh.
Those who failed were more likely to have a history of prior treatment, but genotypic analysis of NRTI resistance mutations was not carried out owing to lack of funds. The relationship between non-adherence, poor absorption of PIs and the selection of NRTI resistance mutations is unknown.
Walsh J et al. Viral drug resistance, adherence and pharmacokinetic indices in HIV-infected patients on successful and failing protease inhibitor (PI) based highly active antiretroviral therapy (HAART). 40th ICAAC, Toronto, abstract 699, 2000.