Article

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

ABSTRACT

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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    • "In effect, the natural tendency to errors of the reverse transcriptase, combined with the high viral replication activity, result in the generation of genetically related viral variations called quasispecies with important implications on the dynamics of the infection[17]. Moreover, one of the major limitations of standard genotyping tests is their inability to detect quasispecies that occur in less than 20–25% of the circulating viral population in a patient[10]. These subpopulations in low-abundance can lead to mutations associated with antiretroviral resistance and can develop rapidly to become predominant under conditions of selective pressure which eventually lead to therapeutic failure[18]. "

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    • "In effect, the natural tendency to errors of the reverse transcriptase, combined with the high viral replication activity, result in the generation of genetically related viral variations called quasispecies with important implications on the dynamics of the infection [17] . Moreover, one of the major limitations of standard genotyping tests is their inability to detect quasispecies that occur in less than 20–25% of the circulating viral population in a patient [10]. These subpopulations in low-abundance can lead to mutations associated with antiretroviral resistance and can develop rapidly to become predominant under conditions of selective pressure which eventually lead to therapeutic failure [18]. "
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