Low level of the K103N HIV-1 above a threshold is associated with virological failure in treatment-naive individuals undergoing efavirenz-containing therapy

Goodman, Derrick; Zhou, Yun; Margot, Nicolas; McColl, Damian J.; Zhong, Lijie; Borroto–Esoda, Katyna; Miller, Michael D.; Svarovskaia, Evguenia S.

doi:10.1097/qad.0b013e3283427dcb

Cited by 92 publications

(105 citation statements)

References 22 publications

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“…Using more-sensitive genotypic assays, different research groups (15,30,32,37,48,58,65) have reported higher proportions of transmitted DRM in ART-naive individuals. The clinical importance of these low-level DRM remains unclear, as they have been associated with clinical consequences in some (21,24,32,36,37,40,46,54,55,63,66,71) but not all (30, 47, 58) studies.Highly sensitive assays for detecting low-frequency DRM include point mutation assays and high-resolution sequencing techniques. Point mutation assays, such as allele-specific PCR, can detect DRM at frequencies as low as 0.01% of the sampled viral population (31,45,53,54), but they do not provide information about the sequence context surrounding a given DRM and may be prone to false positives at the lower level of detection (22).…”

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Detection of Minority Resistance during Early HIV-1 Infection: Natural Variation and Spurious Detection rather than Transmission and Evolution of Multiple Viral Variants

Gianella

Delport

Pacold

et al. 2011

J Virol

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Reports of a high frequency of the transmission of minority viral populations with drug-resistant mutations (DRM) are inconsistent with evidence that HIV-1 infections usually arise from mono-or oligoclonal transmission. We performed ultradeep sequencing (UDS) of partial HIV-1 gag, pol, and env genes from 32 recently infected individuals. We then evaluated overall and per-site diversity levels, selective pressure, sequence reproducibility, and presence of DRM and accessory mutations (AM). To differentiate biologically meaningful mutations from those caused by methodological errors, we obtained multinomial confidence intervals (CI) for the proportion of DRM at each site and fitted a binomial mixture model to determine background error rates for each sample. We then examined the association between detected minority DRM and the virologic failure of first-line antiretroviral therapy (ART). Similar to other studies, we observed increased detection of DRM at low frequencies (average, 0.56%; 95% CI, 0.43 to 0.69; expected UDS error, 0.21 ؎ 0.08% mutations/site). For 8 duplicate runs, there was variability in the proportions of minority DRM. There was no indication of increased diversity or selection at DRM sites compared to other sites and no association between minority DRM and AM. There was no correlation between detected minority DRM and clinical failure of first-line ART. It is unlikely that minority viral variants harboring DRM are transmitted and maintained in the recipient host. The majority of low-frequency DRM detected using UDS are likely errors inherent to UDS methodology or a consequence of error-prone HIV-1 replication.Using standard population-based genotypic assays of HIV from individuals not yet treated with antiretroviral drugs, several studies (43,64,69,76) have estimated the rate of transmitted drug resistance to be between 8 and 27% in countries with the highest rates of antiretroviral therapy (ART) use. In resource-limited settings, in which the introduction of ART has been more recent, the estimated frequency of transmitted drug resistance mutations (DRM) is substantially lower (41). It appears, however, to be increasing in these settings as well (2,14,51). Using more-sensitive genotypic assays, different research groups (15,30,32,37,48,58,65) have reported higher proportions of transmitted DRM in ART-naive individuals. The clinical importance of these low-level DRM remains unclear, as they have been associated with clinical consequences in some (21,24,32,36,37,40,46,54,55,63,66,71) but not all (30, 47, 58) studies.Highly sensitive assays for detecting low-frequency DRM include point mutation assays and high-resolution sequencing techniques. Point mutation assays, such as allele-specific PCR, can detect DRM at frequencies as low as 0.01% of the sampled viral population (31,45,53,54), but they do not provide information about the sequence context surrounding a given DRM and may be prone to false positives at the lower level of detection (22). High-resolution sequencing techniques, such as single ge...

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Detection of Minority Resistance during Early HIV-1 Infection: Natural Variation and Spurious Detection rather than Transmission and Evolution of Multiple Viral Variants

Gianella

Delport

Pacold

et al. 2011

J Virol

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“…For this reason, a series of ultrasensitive HIV-1-genotyping assays, based on deep sequencing (next-generation sequencing [NGS]), have been developed to detect drug-resistant HIV-1 variants at levels below 20% of the viral population in an infected individual (24,(28)(29)(30)(31). Several studies have associated early detection of these minority HIV-1 drug-resistant variants with subsequent treatment failure (32)(33)(34)(35)(36)(37); however, with the advent of single-pill once-a-day (QD) cART regimens, treatment failures in HICs are rare, and the relevance of minority members of the viral population to the ART outcome is still under debate (32,(38)(39)(40)(41).…”

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Low-Frequency Drug Resistance in HIV-Infected Ugandans on Antiretroviral Treatment Is Associated with Regimen Failure

Kyeyune

Gibson

Nankya

et al. 2016

Antimicrob Agents Chemother

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Using this sensitive assay, we observed that 64% (21/33) of these individuals had low-frequency (or minority) drug-resistant variants in the intrapatient HIV-1 population, which correlated with treatment failure. Moreover, the presence of these minority HIV-1 variants was associated with higher intrapatient HIV-1 diversity, suggesting a dynamic selection or fading of drug-resistant HIV-1 variants from the viral quasispecies in the presence or absence of drug pressure, respectively. This study identified lowfrequency HIV drug resistance mutations by deep sequencing in Ugandan patients failing antiretroviral treatment but lacking dominant drug resistance mutations as determined by Sanger sequencing methods. We showed that these low-abundance drugresistant viruses could have significant consequences for clinical outcomes, especially if treatment is not modified based on a susceptible HIV-1 genotype by Sanger sequencing. Therefore, we propose to make clinical decisions using more sensitive methods to detect minority HIV-1 variants.

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“…These undetected resistant associated mutations may cause suboptimal response to ART and lead to rapid emergence of HIV drug resistance, and can be implicated in early treatment failures. [116][117][118][119][120] Unequal exposure to antiretrovirals and treatment interruptions are thought to underlie the development of resistance in some patients. [121][122][123][124][125] Different rates of adherence to medications within a regimen (discordant adherence) combined with varied pharmacokinetics of the agents can lead to viral replication, and subsequent exposure to sub-optimal treatment regimens.…”

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confidence: 99%

Issues in resistance, adherence, and comparative efficacy of the single-tablet regimen combination of tenofovir, emtricitabine, and efavirenz in the management of HIV-1 infection

Rebick¹,

Walmsley²

2012

VAAT

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Abstract:Atripla is the first once-daily, single-tablet, triple-combination antiretroviral therapy. It is recommended for the initial treatment of the naïve patient with human immunodeficiency virus-1 (HIV-1) infection in all current guidelines, based on its proven efficacy in numerous head-to-head randomized clinical trials. Not only has it proven efficacy, but the fixed-dose combination, Atripla, has resulted in an improvement in adherence, quality of life, and satisfaction among naïve as well as virally suppressed patients switching from another regimen. Despite the advantages, tolerability issues can arise that are related primarily to the efavirenz component, which is known to cause central nervous side effects such as dizziness, abnormal dreams, and anxiety. Although generally self-limited, these side-effects can lead to treatment discontinuation in the short-or long-term. Based on the observation of neural tube defects in macaque models, and isolated case reports in human fetuses with first trimester exposure, it is rated as Food and Drug Administration pregnancy category D, and considered as contraindicated in the first trimester of pregnancy where alternatives are available. Given the low genetic barrier of each of the individual components, resistance remains an important issue for patients with poor adherence, but is balanced in part by the long half-life of the drugs. Transmitted resistance is described in up to 16% of newly infected patients in population surveys, and is particularly prevalent in men who have sex with men. Minority variants that may impart resistant to efavirenz are not detected with currently used HIV-1 genotype assays, but nonetheless may also be implicated in patients who fail initial treatment. Several single-tablet regimens are recently licensed or in development that will challenge Atripla as the single-tablet first-line option, but none have shown superior efficacy to date.

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Low level of the K103N HIV-1 above a threshold is associated with virological failure in treatment-naive individuals undergoing efavirenz-containing therapy

Abstract: The presence of K103N mutant virus in plasma above 2000 copies/ml prior to therapy in treatment-naive individuals correlated with increased risk of virologic failure of these efavirenz-containing triple-drug regimens.

Cited by 92 publications

References 22 publications

Detection of Minority Resistance during Early HIV-1 Infection: Natural Variation and Spurious Detection rather than Transmission and Evolution of Multiple Viral Variants

Detection of Minority Resistance during Early HIV-1 Infection: Natural Variation and Spurious Detection rather than Transmission and Evolution of Multiple Viral Variants

Low-Frequency Drug Resistance in HIV-Infected Ugandans on Antiretroviral Treatment Is Associated with Regimen Failure

Issues in resistance, adherence, and comparative efficacy of the single-tablet regimen combination of tenofovir, emtricitabine, and efavirenz in the management of HIV-1 infection

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