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Standard Genotyping Does Not Pick Up All Resistance
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Excerpted from Resistance Before Therapy, Hidden Mutations, and Blips
46th ICAAC, September 27-30, 2006, San Francisco
Mark Mascolini
Closer (clonal) looks show more mutations
Clonal analysis of viral populations from people taking a failing four-nucleoside regimen spotted mutations not seen by standard gene sequencing before treatment began and during virologic failure [9]. Researchers from GlaxoSmithKline and from sites of the COL40263 trial compared standard population sequencing results with clonal analyses in 14 people in whom once-daily Trizivir (AZT/3TC/abacavir) plus tenofovir failed. They defined failure as consecutive viral loads above 400 copies at or after treatment week 24. Pretreatment viral loads were higher and CD4 counts lower in the failure group, and a higher proportion of in the failure group were black (Table 3).
Standard genotyping saw NRTI and NNRTI mutations before treatment in 3 of 14 people who met failure criteria, while clonal analysis spotted pretreatment mutations in these 3 and in an additional 6. Seven of these 14 (4 with mutations detected only by clonal analysis) had pretreatment mutations related to study drugs. Additional thymidine analog mutations (TAMs) or K65R emerged in 6 of these 7 people during treatment with Trizivir/tenofovir.
Among 4 people in whom standard genotyping saw only nonmutant ("wild-type") virus before treatment and nonmutant virus upon failure, clonal analysis disclosed resistance-related mutations in 3 upon failure: L210W (a TAM), M184I (a 3TC mutation), and Y188L (a nonnucleoside mutation not related to drugs in this regimen). In the 10 people in whom standard population sequencing detected resistance mutations upon failure, clonal scrutiny invariably found additional nucleoside-related mutations.
Both standard sequencing and clonal analysis uncovered the tenofovir/abacavir-related K65R mutation when Trizivir/tenofovir stopped working in 2 people who had nonmutant virus or only the V118I substitution before treatment. (The significance of the V118I change in reverse transcriptase without V44D is unknown.[10]) Treatment with standard-dose AZT typically thwarts emergence of K65R, so the researchers speculated that the once-daily AZT dose used in this trial may explain why K65R popped up. Another possibility, they suggested, is that using abacavir with tenofovir allowed K65R to evolve. In 1 person in whom K65R emerged, clonal analysis detected a K70E substitution before therapy. Some research suggests that K70E may favor later selection of K65R.
The Glaxo researchers observed that their clonal analysis bolsters the earlier conclusion that TAMs--and specifically T215F instead of T215Y--are the primary route to resistance among people taking Trizivir with tenofovir. This resistance route differs from the M184V-plus-K65R pathway plotted when tenofovir-containing triple regimens without AZT fail [11-13].
References
9. Rouse E, Preble L, Elion R, et al. Comparison of clonal genotyping and population genotyping of HIV reverse transcriptase at baseline and virologic failure in patients on once-daily Trizivir and tenofovir for <48 weeks. 46th ICAAC. September 27-30, 2006. San Francisco. Abstract H-1005.
10. Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: 2005. Topics HIV Med 2005;13:51-57.
11. Khanlou H, Yeh V, Guyer V, Farthing C. Early virologic failure in a pilot study evaluating the efficacy of therapy containing once-daily abacavir, lamivudine, and tenofovir DF in treatment-naive HIV-infected patients. AIDS Patient Care STDs 2005;19:135-140.
12. Gallant JE, Rodriguez AE, Weinberg WG, et al. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J Infect Dis 2005;192:1921-1930.
13. Jemsek J, Hutcherson P, Harper E. Poor virologic responses and early emergence of resistance in treatment naive, HIV-infected patients receiving a once daily triple nucleoside regimen of didanosine, lamivudine, and tenofovir DF. 11th Conference of Retroviruses and Opportunistic Infections. February 8-11, 2004. San Francisco. Abstract 51.
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