Minority Quasispecies of Drug‐Resistant HIV‐1 That Lead to Early Therapy Failure in Treatment‐Naive and ‐Adherent Patients

Institute of Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany.
Clinical Infectious Diseases (Impact Factor: 8.89). 01/2009; 48(2):239-47. DOI: 10.1086/595703
Source: PubMed


Early virological failure of antiretroviral therapy associated with the selection of drug-resistant human immunodeficiency virus type 1 in treatment-naive patients is very critical, because virological failure significantly increases the risk of subsequent failures. Therefore, we evaluated the possible role of minority quasispecies of drug-resistant human immunodeficiency virus type 1, which are undetectable at baseline by population sequencing, with regard to early virological failure.
We studied 4 patients who experienced early virological failure of a first-line regimen of lamivudine, tenofovir, and either efavirenz or nevirapine and 18 control patients undergoing similar treatment without virological failure. The key mutations K65R, K103N, Y181C, M184V, and M184I in the reverse transcriptase were quantified by allele-specific real-time polymerase chain reaction performed on plasma samples before and during early virological treatment failure.
Before treatment, none of the viruses showed any evidence of drug resistance in the standard genotype analysis. Minority quasispecies with either the M184V mutation or the M184I mutation were detected in 3 of 18 control patients. In contrast, all 4 patients whose treatment was failing had harbored drug-resistant viruses at low frequencies before treatment, with a frequency range of 0.07%-2.0%. A range of 1-4 mutations was detected in viruses from each patient. Most of the minority quasispecies were rapidly selected and represented the major virus population within weeks after the patients started antiretroviral therapy. All 4 patients showed good adherence to treatment. Nonnucleoside reverse-transcriptase inhibitor plasma concentrations were in normal ranges for all 4 patients at 2 separate assessment times.
Minority quasispecies of drug-resistant viruses, detected at baseline, can rapidly outgrow and become the major virus population and subsequently lead to early therapy failure in treatment-naive patients who receive antiretroviral therapy regimens with a low genetic resistance barrier.

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Available from: Huldrych F Günthard, Sep 29, 2015
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    • "To estimate in vivo fitness landscapes and without direct observation of the growth kinetics of the viral population, an evolutionary model is required that links fitness to haplotype frequencies. Here we employ, for this purpose, the quasispecies model, an established model of intrahost viral evolution (Eigen and Schuster 1977; Burch and Chao 2000; Vignuzzi et al. 2005; Metzner et al. 2009; Domingo et al. 2012), which is mathematically tractable. One of the predictions of quasispecies theory that has stood the test of time is the existence of an error threshold in viral replication. "
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    ABSTRACT: Fitness is a central quantity in evolutionary models of viruses. However, it remains difficult to determine viral fitness experimentally, and existing in vitro assays can be poor predictors of in vivo fitness of viral populations within their hosts. Next-generation sequencing can nowadays provide snapshots of evolving virus populations, and these data offer new opportunities for inferring viral fitness. Using the equilibrium distribution of the quasispecies model, an established model of intra-host viral evolution, we linked fitness parameters to the composition of the virus population, which can be estimated by next-generation sequencing. For inference, we developed a Bayesian Markov Chain Monte Carlo method to sample from the posterior distribution of fitness values. The sampler can overcome situations where no maximum likelihood estimator exists, and it can adaptively learn the posterior distribution of highly correlated fitness landscapes without prior knowledge of their shape. We tested our approach on simulated data and applied it to clinical HIV-1 samples to estimate their fitness landscapes in vivo. The posterior fitness distributions allowed for differentiating viral haplotypes from each other, for determining neutral haplotype networks, in which no haplotype is more or less credibly fit than any other, and for detecting epistasis in fitness landscapes. Our implemented approach, called QuasiFit, is available at Copyright © 2014, The Genetics Society of America.
    Genetics 11/2014; 199(1). DOI:10.1534/genetics.114.172312 · 5.96 Impact Factor
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    • "The primary resistance rate was 17.7%, which is similar to the rate (17.0%) of newly diagnosed individuals reported by Johnson et al [20], and higher than the rate (11.6%) reported by Novak et al [34], It is also higher than the rate in the United States (10%) [35]and the rate reported by Wang X, et al [36] and Liao L, et al [37] in China (2.7%–3.8%). However, this rate is lower than that in Canada (18.5% in 1999–2000, 27.6% in 2001)[38]–[39]. "
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    ABSTRACT: Natural drug resistance is a major cause of antiviral treatment failure. The characteristics of HIV-1 natural drug resistance-associated mutations in former paid blood donors in Henan Province remain unclear. One hundred and fifty HIV-1-positive plasma samples were collected. Plasma viral RNA was extracted for pol gene amplification and sequencing. The sequencing results were submitted to the HIV-1 drug resistance database for drug-resistance analysis. The rates of natural drug resistance and resistance-associated mutations were 17.7% (19/107) and 40.2% (43/107), respectively. The rates of PI major, PI minor, NRTI, and NNRTI mutations were: 0, 30.8% (33/107), 10.3% (11/107), and 18.7% (20/107), respectively. Nine cases (8.4%) had both NRTI and NNRTI resistance-associated mutations. Seven cases (6.5%) had PI minor, NRTI and NNRTI resistance-associated mutations. NNRTI resistance was the most serious, followed by NRTI resistance and PI resistance. Polymorphism mutation sites with mutation rates in the protease region higher than 60.0% were: L63A/P/S/T 89.7%, V77I 82.2%, I72E/M/K/T/V 80.4%, I93L 75.7%, and E35D 72.9%. Polymorphism mutation sites with mutation rates in the RT region higher than 60.0% were: I135A/L/M/R/T/V 93.5%, T200A/E/I/P/V 89.7%, Q278E/K/N/T 88.8%, S162C/Y 82.2%, and K277R/S 66.4%. The distribution of 107 gene sequences was scattered, with some drug-resistant strains grouped in the same cluster. The natural drug resistance mutation rate of HIV-1 in former paid blood donors in Henan Province was 17.7%, with NNRTI resistance the most serious. The distribution of drug-resistant strains was scattered, with some correlations found in certain resistance loci.
    PLoS ONE 02/2014; 9(2):e89291. DOI:10.1371/journal.pone.0089291 · 3.23 Impact Factor
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    • "There is legitimate concern that minority drug-resistant mutants may be selected during the initial HIV-1 RNA decay phase following antiretroviral therapy initiation, when decreasing but still detectable HIV-1 RNA levels transiently coexist with suboptimal drug levels. Studies using allele-specific PCR suggested that drug-resistant HIV-1 might be selected and replicate in the first weeks of suppressive antiretroviral therapy (ART) [1,2]. If they were confirmed, such observations would support using intensified ART regimens to accelerate viremia suppression and curtail drug resistance evolution, but not only in treatment-naïve subjects initiating first-line ART. "
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    ABSTRACT: There is legitimate concern that minority drug-resistant mutants may be selected during the initial HIV-1 RNA decay phase following antiretroviral therapy initiation, thus undermining efficacy of treatment. The goal of this study was to characterize viral resistance emergence and address viral population evolution during the first phase of viral decay after treatment containing initiation. 454 sequencing was used to characterize viral genetic diversity and polymorphism composition of the HIV-1 integrase gene during the first two weeks following initiation of raltegravir-containing HAART in four ART-experienced subjects. No low-prevalence Raltegravir (RAL) drug resistance mutations (DRM) were found at baseline. All patients undergoing treatment received a fully active ART according to GSS values (GSS >= 3.5). No emergence of DRM after treatment initiation was detected. Longitudinal analysis showed no evidence of any other polymorphic mutation emergence or variation in viral diversity indexes. This suggests that fully active salvage antiretroviral therapy including raltegravir achieves a complete blockade of HIV-1 replication in plasma. It is unlikely that raltegravir-resistant HIV-1 may be selected in plasma during the early HIV-1 RNA decay after treatment initiation if the administered therapy is active enough.
    Virology Journal 12/2013; 10(1):350. DOI:10.1186/1743-422X-10-350 · 2.18 Impact Factor
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