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Low-Level Transmitted K103N Mutation Predicts Virologic Failure
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7th European HIV Drug Resistance Workshop, March 25-27, 2009, Stockholm
Mark Mascolini
Pretreatment low-frequency K103N mutations correlated with virologic failure of a nonnucleoside-based regimen in a British case-control study [1]. Four of 7 patients had transmitted nonnucleoside resistance mutations that could be detected only with a real-time PCR assay that identifies virus making up 0.3% to 1% of a viral population. Standard bulk sequencing sees virus only when it makes up about 20% or more of a viral population.
Ana Garcia-Diaz and colleagues at London's Royal Free Hospital and the US Centers for Disease Control compared 18 patients whose first-line nonnucleoside regimen failed and 75 patients without first-line nonnucleoside failure. The investigators matched the 18 cases and 75 controls for type of regimen, duration of follow-up, pretreatment CD4 count (above or below 200), and pretreatment viral load (above or below 65,000 copies).
Everyone had established HIV infection when diagnosed, and all began treatment with efavirenz or nevirapine plus two or more nucleosides from 1998 through 2007. The investigators analyzed pretreatment and failure samples with standard sequencing and real-time PCR targeting the reverse transcriptase mutations K65R, K103N, Y181C, M184V, and G190A. K103N, Y181C, and G190A are nonnucleoside-related mutations.
None of the 75 control patients had detectable pretreatment mutations, while 7 of 18 cases (39%) did. Standard sequencing detected high-frequency K103N (K103Nhigh) in 2 patients and high-frequency G190A (G190Ahigh) in 1 patient. Four of 7 patients had only low-frequency K103N (K103Nlow). No one had more than a single nonnucleoside mutation. Either high-frequency mutations (P = 0.006) or low-frequency mutations (P = 0.001) predicted virologic failure. An analysis combining high- and low-frequency mutations yielded a more robust prediction of virologic failure (P < 0.0001).
Standard genotyping at virologic failure revealed the pretreatment mutation plus additional reverse transcriptase mutations in 5 patients, including the 1 with G190Ahigh, 2 with K103Nhigh, and 2 with K103Nlow. At failure, the other 2 patients with K103Nlow before treatment had K103R or V106M plus F227L--and additional reverse transcriptase mutations. Thus low-frequency pretreatment mutations did not re-emerge upon failure in every patient. Still, these results add to published data correlating some low-level pretreatment mutations with mutations recorded at failure [2,3].
A retrospective study of 160 antiretroviral-naive patients in Germany's Nordrhein-Westfalen region, reported separately by NATAP, found low-frequency K103N viral populations in 12 of them (7.5%) [4]. This analysis relied on allele-specific real-time PCR with a sensitivity cutoff of 0.5%. When the investigators reduced the cutoff to 0.1%, 16.5% of patients appeared to have low-frequency K103N before treatment. But low-level pretreatment K103N did not cause failure of nonnucleoside-based therapy in 4 people who started such a regimen.
References
1. Garcia-Diaz A, Johnson JA, Fox ZV, et al. Low-frequency mutations strengthen the impact of transmitted drug resistance on virological responses to first-line efavirenz or nevirapine based antiretroviral therapy. 7th European HIV Drug Resistance Workshop, March 25-27, 2009, Stockholm. Abstract 113.
2. Johnson JA, Li JF, Wei X, et al. Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naïve populations and associate with reduced treatment efficacy. PLoS Med. 2008;5(7):e158.
3. Metzner KJ, Giulieri SG, Knoepfel SA, et al. Minority quasispecies of drug-resistant HIV-1 that lead to early therapy failure in treatment-naive and -adherent patients. Clin Infect Dis. 2009;48:239-247.
4. Braun P, Ehret R, Wiesmann F, Metzner KJ, Knechten H. Prevalence of the K103N mutation at low frequencies in antiretroviral treatment-naive patients in Germany 2008. 7th European HIV Drug Resistance Workshop, March 25-27, 2009, Stockholm. Abstract 71.
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