Efficient Suppression of Minority Drug‐Resistant HIV Type 1 (HIV‐1) Variants Present at Primary HIV‐1 Infection by Ritonavir‐Boosted Protease Inhibitor–Containing Antiretroviral Therapy

Metzner, Karin J.; Rauch, Pia; Wyl, Viktor von; Leemann, Christine; Grube, Christina; Küster, Herbert; Böni, Jürg; Weber, Rainer; Günthard, Huldrych F.

doi:10.1086/651136

Cited by 53 publications

(54 citation statements)

References 45 publications

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“…These studies show that minority M184V carrying HIV-1 variants are more frequently detectable than minority K103N carrying HIV-1 variants. 15,20,25,30 We and others have previously shown that the detection of minority NNRTI-resistant HIV-1 variants prior to ART can be associated with an increased risk for virological failure in patients receiving regimens containing an NNRTI. 14,16,17,[31][32][33] Although in the present study a total of 65 patients (44.5%) were treated with an NNRTI-containing regimen, only 2 of the 8 patients who harbored the K103N mutation at low frequencies received an NNRTI.…”

Section: Discussionmentioning

confidence: 99%

“…in treatment-naïve patients, where a correlation between NRTIor NNRTI resistance mutations at low frequencies and virological failure was not observed in patients receiving PIs. 15,17,20 In summary, although there is some evidence that pre-existing NNRTI resistance mutations at low frequencies can compromise the success of NNRTI-containing ART regimens, the importance of drug-resistant minorities for the outcome of ART is still a matter of controversy. This is a highly complex issue and multiple factors have to be considered, for instance, absolute copy numbers of the minority drug-resistant HIV-1 variants (mutational load), possible linkage of drug resistance mutations, and genetic barriers to resistance.…”

Section: Discussionmentioning

confidence: 99%

“…23 Resistance testing by K65R, K103N, and M184V AS-PCR assays was performed as previously described in detail. 16,20,24,25 Samples were repeated when positive for one mutation. Quality and accuracy controls were performed as previously described.…”

Section: Methodsmentioning

confidence: 99%

“…13 The impact of pre-existing minority drug-resistant HIV-1 variants on first-line ART remains unresolved. [14][15][16][17][18][19][20] Contradictory results in treatment-naïve patients might be due to differences in the patient populations and the antiretroviral regimens, which differ in respect to their genetic resistance barriers. 21 In this study within the German Truvada Cohort, we wanted to investigate the prevalence of the key drug resistance mutations K65R, K103N, and M184V at low frequencies and their possible impact on the clinical outcome of first-line ART in chronically HIV-1 infected patients.…”

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confidence: 99%

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Prevalence of key resistance mutations K65R, K103N, and M184V as minority HIV-1 variants in chronically HIV-1 infected, treatment-naïve patients

Metzner

Rauch

Braun

et al. 2011

Journal of Clinical Virology

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Prevalence of key resistance mutations K65R, K103N, and M184V as minority HIV-1 variants in chronically HIV-1 infected, treatment-naïve patients

Metzner

Rauch

Braun

et al. 2011

Journal of Clinical Virology

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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.…”

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confidence: 99%

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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Low-Frequency HIV-1 Drug Resistance Mutations and Risk of NNRTI-Based Antiretroviral Treatment Failure

Paredes

Ribaudo

et al. 2011

JAMA

333

307

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Context Evidence regarding the impact of minority, or low frequency, HIV-1 drug-resistant variants on the effectiveness of first-line antiretroviral treatment (ART) is conflicting. Objective To evaluate the association of pre-existing HIV-1 minority drug-resistant variants with risk of first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral virologic failure. Data Sources We searched published and unpublished studies in MEDLINE (1966 through December, 2010), EMBASE (1974 through December, 2010), conference abstracts, and article references. Authors of all studies were contacted for detailed laboratory, ART, and adherence data. Study Selection and Data Abstraction Studies involving ART-naive participants initiating NNRTI-based regimens were included. Participants were included if all drugs in their ART regimen were fully active by standard HIV population sequencing. Cox proportional hazard models using pooled patient-level data were used to estimate the risk of virologic failure based on a Prentice weighted case-cohort analysis stratified by study. Data Synthesis Individual data from 10 studies and 985 participants were available for the primary analysis. Minority HIV-1 drug resistance mutations were associated with an increased risk of virologic failure (HR 2.3 [95% CI, 1.7–3.3], P<0.001) after controlling for medication adherence, ethnicity, baseline CD4 cell count and plasma HIV-1 RNA levels. The increased risk of virologic failure was most strongly associated with minority variants resistant to NNRTIs (HR 2.6 [95% CI, 1.9–3.5], P<0.001). Among participants from the cohort studies, 35% of those with detectable minority variants experienced virologic failure as compared to 15% of those without minority variants. The presence of minority variants was associated with 2.5–3 times the risk of virologic failure at either ≥95% or <95% overall medication adherence. A dose-dependent increased risk of virologic failure was found in participants with a higher proportion or quantity of drug-resistant variants. Conclusion In this pooled analysis, minority HIV-1 resistance mutations, particularly involving NNRTI-resistance, were significantly associated with a dose-dependent increased risk of virologic failure with first-line ART.

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Efficient Suppression of Minority Drug‐Resistant HIV Type 1 (HIV‐1) Variants Present at Primary HIV‐1 Infection by Ritonavir‐Boosted Protease Inhibitor–Containing Antiretroviral Therapy

Cited by 53 publications

References 45 publications

Prevalence of key resistance mutations K65R, K103N, and M184V as minority HIV-1 variants in chronically HIV-1 infected, treatment-naïve patients

Prevalence of key resistance mutations K65R, K103N, and M184V as minority HIV-1 variants in chronically HIV-1 infected, treatment-naïve patients

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 HIV-1 Drug Resistance Mutations and Risk of NNRTI-Based Antiretroviral Treatment Failure

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