Antiretroviral Drug Resistance Testing in Adult HIV‐1 Infection: 2008 Recommendations of an International AIDS Society–USA Panel

Hirsch, Martin S.; Günthard, Huldrych F.; Schapiro, Jonathan; Brun‐Vézinet, Françoise; Clotet, Bonaventura; Hammer, Scott M.; Johnson, Victoria A.; Kuritzkes, Daniel R.; Mellors, John W.; Pillay, Deenan; Yéni, Patrick; Jacobsen, Donna M.; Richman, Douglas D.

doi:10.1086/589297

Cited by 505 publications

(497 citation statements)

References 191 publications

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“…Based on a large knowledge accumulated and published by many authors about PR and RT mutations in the last 10 years, genotype report helps to target selection of new drugs after initial drug failure. [11][12][13] Internationally, reports estimating the prevalence of antiretroviral resistance have shown epidemiological features of the global burden of resistance through the years.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 genotypic resistance profile of patients failing antiretroviral therapy in Paraná, Brazil

Toledo¹,

Carvalho²,

Romagnoli³

et al. 2010

Braz J Infect Dis

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Antiretroviral therapy (ART) has reduced morbidity and mortality related to human immunodeficiency virus (HIV) infection, but in spite of this advance, HIV mutations decrease antiretroviral susceptibility, thus contributing to treatment failure in patients. Genotyping HIV-1 allows the selection of new drugs after initial drug failure. This study evaluated the genotypic profi le of HIV-1 isolates from treated (drug-experienced) patients in Paraná, Brazil. The prevalence of mutations in reverse transcriptase (RT) and protease (PR) genes were assessed. We analyzed 467 genotypes of patients with HIV-1 viral loads above 1,000 copies/mL. Mutations at HIV-1 RT and PR genes and previously used ART regimens were recorded. The most prevalent RT mutations were: 184V (68.31%), 215YF (51.6%), 103NS (46%), 41L (39.4%), 67N (38.54%), 210W (23.5%), 190ASE (23.2%), and 181C (17.4%). PR mutations were 90M (33.33%), 82ATFS (29%), 46I (26.8%) and 54V (22.2%). The prevalence of mutations was in line with previous national and international reports, except to nonnucleoside analogue reverse transcriptase inhibitors related mutations, which were more prevalent in this study. Previous exposure to antiretroviral drugs was associated with genotypic resistance to specifi c drugs, leading to treatment failure in HIV patients.

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Section: Introductionmentioning

confidence: 99%

HIV-1 genotypic resistance profile of patients failing antiretroviral therapy in Paraná, Brazil

Toledo¹,

Carvalho²,

Romagnoli³

et al. 2010

Braz J Infect Dis

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“…HIV/AIDS | pharmacology | virology | highly active antiretroviral therapy | evolution W ith suboptimal treatment, drug-resistant HIV-1 evolves rapidly (1)(2)(3)(4)(5)(6)(7). Resistance results from mutations introduced by the error-prone HIV-1 reverse transcriptase (RT) (8)(9)(10).…”

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confidence: 99%

Dose–response curve slope is a missing dimension in the analysis of HIV-1 drug resistance

Sampah¹,

Shen

Jilek³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

129

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HIV-1 drug resistance is a major clinical problem. Resistance is evaluated using in vitro assays measuring the fold change in IC 50 caused by resistance mutations. Antiretroviral drugs are used at concentrations above IC 50 , however, and inhibition at clinical concentrations can only be predicted from IC 50 if the shape of the dose-response curve is also known. Curve shape is influenced by cooperative interactions and is described mathematically by the slope parameter or Hill coefficient (m). Implicit in current analysis of resistance is the assumption that mutations shift dose-response curves to the right without affecting the slope. We show here that m is altered by resistance mutations. For reverse transcriptase and fusion inhibitors, single resistance mutations affect both slope and IC 50 . For protease inhibitors, single mutations primarily affect slope. For integrase inhibitors, only IC 50 is affected. Thus, there are fundamental pharmacodynamic differences in resistance to different drug classes. Instantaneous inhibitory potential (IIP), the log inhibition of single-round infectivity at clinical concentrations, takes into account both slope and IC 50 , and thus provides a direct measure of the reduction in susceptibility produced by mutations and the residual activity of drugs against resistant viruses. The standard measure, fold change in IC 50 , does not correlate well with changes in IIP when mutations alter slope. These results challenge a fundamental assumption underlying current analysis of HIV-1 drug resistance and suggest that a more complete understanding of how resistance mutations reduce antiviral activity requires consideration of a previously ignored parameter, the dose-response curve slope.HIV/AIDS | pharmacology | virology | highly active antiretroviral therapy | evolution

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“…[1][2][3][4][5][6][7][8] Resistance testing for chronically HIV-infected individuals is currently recommended at the time of the first evaluation and at treatment initiation. 9 The prevalence of primary resistance varies by geographic region and may be influenced by local demographics, HIV risk factors, and the penetration of antiretroviral therapy (ART) in the local area. 9 Relatively few studies have been conducted outside large metropolitan areas where the prevalence and/or patterns of resistance may be different.…”

Section: Introductionmentioning

confidence: 99%

“…9 The prevalence of primary resistance varies by geographic region and may be influenced by local demographics, HIV risk factors, and the penetration of antiretroviral therapy (ART) in the local area. 9 Relatively few studies have been conducted outside large metropolitan areas where the prevalence and/or patterns of resistance may be different. Knowledge of local resistance data may help to follow trends in the prevalence of resistance and result in a better understanding of the current HIV epidemic.…”

Section: Introductionmentioning

confidence: 99%

Low Prevalence of Primary HIV Resistance in Western Massachusetts

Iarikov

Irizarry-Acosta

Martorell³

et al. 2010

Journal of the International Association of Physicians in AIDS

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Most studies of primary antiretroviral (ARV) resistance have been conducted in large metropolitan areas with reported rates of 8% to 25%. We collected data on 99 HIV-1-infected antiretroviral-naive patients from several sites in Springfield, MA, who underwent genotypic resistance assay between 2004 and 2008. Only major resistance mutations per International AIDS Society-USA (IAS-USA) drug resistance mutations list were considered. The prevalence of resistance was 5% (5 of 99). Three patients had one nonnucleoside reverse transcriptase inhibitor (NNRTI) mutation: 103N, 103N, and 190A, 1 patient had a protease inhibitor (PI) mutation: 90M; and 1 patient had 3-class resistance with NNRTI: 181C, 190A, PI: 90M, and nucleoside analogue reverse transcriptase inhibitor (NRTI): 41L, 210W. Mean time from HIV diagnosis to resistance testing was shorter in patients with resistance versus those without: 9 (range 0.3-42 months) versus 27 (range 0.1-418 months), P ¼ .11. There was a trend to lower mean CD4 count in those with resistance, 170 versus 318 cells/mm 3 , P ¼ .06. No differences were noted in gender, age, HIV risk category, or HIV RNA level. The low prevalence of primary resistance may be explained by differences in demographic and risk factors or may reflect the time from infection to resistance testing. Our findings emphasize the importance of continued resistance surveillance.

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Antiretroviral Drug Resistance Testing in Adult HIV‐1 Infection: 2008 Recommendations of an International AIDS Society–USA Panel

Cited by 505 publications

References 191 publications

HIV-1 genotypic resistance profile of patients failing antiretroviral therapy in Paraná, Brazil

HIV-1 genotypic resistance profile of patients failing antiretroviral therapy in Paraná, Brazil

Dose–response curve slope is a missing dimension in the analysis of HIV-1 drug resistance

Low Prevalence of Primary HIV Resistance in Western Massachusetts

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