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Why Do British Docs Follow Antiretroviral Rules Less and Less?
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11th European AIDS Conference
October 24-27, 2007
Madrid
Mark Mascolini
British clinicians switching people from a failing first-line regimen follow national guideline advice less than half the time, according to results of a 6480-person UK CHIC cohort study [1]. And clinicians saw eye-to-eye with guideline gurus less and less in more recent years. Meanwhile, many clinicians delayed switching to a second regimen after the first combination failed. But sound thinking--not thoughtless bravado--may explain some of this apparent antiretroviral roguery, a few HIV experts proposed after Caroline Sabin's talk at the 11th European AIDS Conference.
Sabin scrutinized 7931 antiretroviral-naive people who started their first combination from 1998 through 2005. Slightly more than half began a nonnucleoside combination, one third began a protease inhibitor (PI), and the rest started three nucleosides or a PI plus a nonnucleoside. Among 6480 people who reached a viral load below 400 copies within 6 months of starting therapy, 694 (10.7%) had a confirmed rebound in a median 1.4 years.
At the end of follow-up, physicians of 198 rebounders (28.5%) still had not prescribed a fresh regimen, while 145 (20.9%) added only one active drug, and 36 (5.2%) recycled old antiretrovirals. Six months after viral rebound, 36% of cohort members continued taking a failing regimen, as did 21% after 1 year and 10% after 2 years.
Gender, HIV transmission group, current antiretroviral regimen, number of drugs in the current regimen, and previous drug substitutions did not affect whether a physician switched after first-line failure. Switching proved 17% less likely for every 100-cell higher latest CD4 count (P < 0.001) and 28% more likely for every 10-fold higher latest viral load (P < 0.001). Every added 5 years of patient age made switching 6% more likely, but that correlation stopped short of statistical significance (P = 0.09). Sabin also uncovered an 8% trend toward more switching in 2000-2002 and 2003-2005 than in 1997-1999.
That last finding suggests more aggressive failure management in more recent years. But other results indicate widespread rebellion against British national guidelines among physicians who do swap out drugs from a failing regimen. Among 496 regimen changes, Sabin rated only 242 of them (48.8%) in step with guidelines. Meanwhile, 46 regimen revamps (9.3%) marshaled fewer than two new (active) antiretrovirals, 73 changes (14.7%) involved no new drug class, and 135 changes (27.2%) relied on fewer than two new drugs and no new class.
On top of that, guideline adherence got worse and worse after the turn of the millennium. With 1998-2000 as the reference years, Sabin found guideline-appropriate switches 40% less likely in 2001-2003 and 51% less likely in 2004-2005. Both backslides, however, lacked statistical significance.
Every 100-cell higher CD4 count at rebound made guideline adherence 14% less likely (P = 0.02), and every 10-fold higher viral load at rebound made adherence 48% less likely (P < 0.001). Failure of a nonnucleoside regimen made a guideline-dictated switch 2.25 times more likely (P < 0.001), while an earlier drug substitution made a guideline-sanctioned switch 80% less likely (P < 0.001).
Sabin surmised her CD4 and viral load correlations may mean clinicians track these beacons at failure then adopt a wait-and-see attitude, making a drug switch only when they see further deterioration. She suggested four other factors that may militate against strict guideline adherence:
- Patient choice
- Uncertainty about the significance of low-level viremia or viral blips
- Individual resistance test results supporting a departure from guidelines, for example, the finding of resistance to only one drug in a failing regimen
- Availability of new boosted PIs with limited cross-resistance making out-of-class changes unnecessary
Canadian clinician John Gill proposed that concurrent illnesses not uncovered in this analysis, such as TB, may warrant a delay in antiretroviral changes. He also suggested some physicians apparently dragging their heels in building backup regimens may just be waiting for two or more potent antiretroviral options. But Sabin maintained that clinicians still have plenty of options after a first-regimen failure.
Resistance expert and session cochair Andrea DeLuca endorsed Sabin's speculation that some clinicians may not follow the two-new-drugs rule when switching because prompt genotyping indicates resistance to only one drug in a failing regimen. In that case a single drug swap could make more sense than two.
Reference
1. Lee KJ, Dunn DT, Sabin CA, et al. Antiretroviral changes after viral load rebound in the UK Collaborative HIV Cohort (CHIC) study. European AIDS Conference. October 24-27, 2007. Madrid. Abstract PS3/4.
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