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Cumulative Resistance Catalog Gives Clearer Picture of Salvage Picks
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XVII International HIV Drug Resistance Workshop
June 10-14, 2008, Sitges, Spain
Mark Mascolini
Accounting for all resistance mutations that ever evolved during a patient's treatment history provided a substantially richer survey of resistance risks than did the latest resistance test alone in an 800-person Swiss analysis [1].
The findings confirm earlier reports of potentially important differences between a "historical genotype" that includes all mutations ever recorded and the most recent genotype [2,3]. Standard genotypic assays usually miss mutations that make up less than 20% of a person's viral population. But when mutations persist at low levels, they can easily re-emerge if a person starts a drug that provokes such mutations.
Sabine Yerly and Swiss HIV Cohort Study collaborators examined mutation data from 813 people with genotyping results on file from 1991 to 2008, putting them into three groups:
· 616 people with at least two sequences including at least one with a nucleoside-related mutation
· 110 people with at least two sequences including at least one with a nonnucleoside-related mutation
· 87 people with at least two sequences including at least one with a protease inhibitor-related mutation
These patients had a median of 5 samples (interquartile range [IQR] 2 to 6) and a median follow-up of 46 months (IQR 20 to 76).
Significantly more mutations appeared on the cumulative list than on the latest list for nucleoside mutations, nonnucleoside mutations, indinavir mutations, and saquinavir mutations. Measuring changes in resistance levels (from sensitive to intermediate or resistant, and from intermediate to resistant) when accounting for cumulative mutations, Yerly recorded significantly worse resistance rates for abacavir, didanosine (ddI), lamivudine (3TC), stavudine (d4T), tenofovir, zidovudine (AZT), efavirenz, etravirine, nevirapine, indinavir, and saquinavir.
In people taking these drugs--or amprenavir or lopinavir--median numbers of mutations were always higher with cumulative analysis than with the latest genotype:
· ddI, AZT, and d4T: 3 versus 0
· 3TC: 1 versus 0
· Tenofovir: 3 versus 1
· Abacavir: 5 versus 2
· Efavirenz and nevirapine: 2 versus 0
· Etravirine: 4 versus 2
· Indinavir: 4 versus 1
· Saquinavir: 4 versus 2
· Lopinavir: 7 versus 5
· Amprenavir: 5 versus 2
Yerly and coworkers argued that cumulative analysis of resistance mutations offers "an additional tool" when trying to pick a rescue regimen, particularly in people who have tried multiple antiretroviral medleys. They cautioned, though, that the cumulative approach can also be misleading because compensatory or antagonistic mutations may alter the impact of current or archived mutations.
Earlier work by Italian investigators offered evidence that a resistance profile accounting for failure of earlier regimens predicts salvage failure better than the latest genotype [2]. Comparing cumulative versus current mutations in 1734 people, researchers in British Columbia found that the most recent genotype consistently underestimates mutation rates [3].
References
1. Yerly S, Michel PA, Emler S, et al. Cross-sectional versus cumulative interpretation of HIV-1 drug resistance mutations. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 100.
2. Zaccarelli M, Lorenzini P, Tozzi V, et al. Are current or archived resistance mutations predictive of treatment failure in heavily pre-treated HIV patients? 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 42. (http://www.natap.org/2008/EHDRW/EHDRW_11.htm)
3. Harrigan PR, Wynhoven B, Brumme ZL, et al. HIV-1 drug resistance: degree of underestimation by a cross-sectional versus a longitudinal testing approach. J Infect Dis. 2005;191:1325-1330.
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