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Most Low-Level Pretreatment Mutations Did Not Affect Outcome in PI Trial
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Mark Mascolini
XVIII International Drug Resistance Workshop, June 9-13, 2009, Fort Myers, Florida
People infected with levels of mutation-laden virus too small to be seen by standard genotyping responded to first-line atazanavir/ritonavir or lopinavir/ritonavir as well as people without pretreatment mutations, according to a case-control study of CASTLE trial participants [1]. There was one exception to this rule: Patients with extensive nucleoside mutations before treatment did seem to run a higher risk of failure with these protease inhibitor (PI) regimens, both of which contained tenofovir/emtricitabine (TDF/FTC).
CASTLE randomized 883 previously untreated people on five continents to once-daily atazanavir/ritonavir or twice-daily lopinavir/ritonavir, both with TDF/FTC [2]. After 48 weeks, about three quarters in each treatment arm had a viral load under 50 copies.
The new study used ultradeep pyrosequencing to probe pretreatment samples for resistance mutations too scarce to be noticed by standard sequencing. Max Lataillade (Bristol-Myers Squibb and Yale University) and coworkers focused on samples from all 53 people who had virologic failure by CASTLE week 48 and 95 samples from randomly selected virologic responders matched to nonresponders by regimen, pretreatment CD4 count, and viral load. The investigators counted mutations that appear on the 2009 World Health Organization list of transmitted mutations [3].
Of the 148 samples analyzed, ultradeep sequencing was successful in 141 samples, 51 in the failure group and 90 in the comparison group. While 86 ultradeep-sequenced samples were HIV-1 subtype B, 55 were other HIV-1 subtypes and circulating recombinant forms.
Forty-three pretreatment viruses (30.5%) bore one or more resistance mutations, about triple the rate seen in analyses of pretreatment virus using standard genotyping. Twenty-two of these 43 samples (51%) has mutations comprising less than 20% of a person's viral population--the often-cited cutoff with standard genotyping. Prevalence of pretreatment mutations was similar in subtype B virus (30%) and non-B variants (31%).
Lataillade reported the following rates of transmitted resistance mutations:
· 18 people (12.8%) with multiclass mutations
· 16 people (11.3%) with nonnucleoside mutations (15 with at least one K103N, Y181C/I, or G190A/E)
· 35 people (24.8%) with nucleoside mutations
· 26 people (18.4%) with thymidine analog mutations (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E)
· 9 people (6.4%) with M184V/I
· 2 people (1.4%) with K65R
Pretreatment mutation rates were statistically equivalent in virologic responders (33.3%) and people with virologic failure (25.5%). Proportions of responders and nonresponders with nucleoside mutations were 24.4% and 25.5%, with nonnucleoside mutations 11.1% and 11.8%, and with PI mutations 14.4% and 2.0%.
Among the 9 people with M184V/I before beginning therapy, 7 (77.8%) had mutation levels below 20%, and 5 (55.5%) had virologic failure at weeks 48 and 96. Three people with M184V/I and virologic failure also had thymidine analog mutations, and 1 had K65R plus thymidine analog mutations. Among 16 people with multiple thymidine analog mutations (11.3%), 7 (43.7%) had virologic failure.
Fourteen people (9.9%) had protease inhibitor mutations, 11 of them (78.6%) at a level below 20%. Only one of those 14 (7.1%) did not respond to the ritonavir-boosted PI. Another person with multiple PI and nucleoside mutations at levels above 20% endured virologic failure in CASTLE.
References
1. Lataillade M, Chicarella J, Yang R, et al. Prevalence and clinical significance of transmitted drug resistant HIV mutations by ultra-deep and sequencing in HIV-infected ARV-naive USA. subjects in CASTLE study XVIII International Drug Resistance Workshop. June 9-13, 2009. Fort Myers, Florida. Abstract 42.
2. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008;372:646-655.
3. Bennett DE, Camacho RJ, Otelea D, et al. Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update. PLoS One. 2009;4(3):e4724.
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