Transmission of HIV-1 Drug-Resistant Variants: Prevalence and Effect on Treatment Outcome

Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark.
Clinical Infectious Diseases (Impact Factor: 9.42). 02/2010; 50(4):566-73. DOI: 10.1086/650001
Source: PubMed

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) drug resistance is an important threat to the overall success of antiretroviral therapy (ART). Because of the limited sensitivity of commercial assays, transmitted drug resistance (TDR) may be underestimated; thus, the effect that TDR has on treatment outcome needs to be investigated. The objective of this study was to investigate the prevalence of TDR in HIV-infected patients and to evaluate the significance of TDR with respect to treatment outcome by analyzing plasma viral RNA and peripheral blood mononuclear cell proviral DNA for the presence of drug resistance mutations.
In a prospective study, we investigated the level of TDR in 61 patients by comparing the results of a sensitive multiplex-primer-extension approach (termed HIV-SNaPshot) that is capable of screening for 9 common nucleoside reverse-transcriptase inhibitor and nonnucleotide reverse-transcriptase inhibitor mutations with those of a commercial genotyping kit, ViroSeq (Abbott).
Twenty-two patients were found to carry mutations. More patients with TDR were identified by the HIV-SNaPshot assay than by ViroSeq analysis (33% vs 13%; [P=.015). There was no significant difference in the time from initiation of ART to virological suppression between susceptible patients and those carrying low- or high-level resistance mutations (mean +/- standard deviation, 128 +/- 59.1 vs 164.9 +/- 120.4; P=.147). Furthermore, analyses of CD4 cell counts showed no significant difference between these 2 groups 1 year after the initiation of ART (mean, 184 vs 219 cells/microL; P=.267).
We found the prevalence of TDR in recently infected ART-naive patients to be higher than that estimated by ViroSeq genotyping alone. Follow-up of patients after treatment initiation showed a trend toward there being more clinical complications for patients carrying TDR, although a significant effect on treatment outcome could not be demonstrated. Therefore, the clinical relevance of low-abundance resistant quasispecies in early infection is still in question.

  • Source
    • "Prevalence in the treatment-naı¨ve patients was assessed for the 16 RPV-associated RAMs listed in the IAS-USA recommendations: K101E/P, E138A/G/ K/Q/R, V179L, Y181C/I/V, Y188L, H221Y, F227C, and M230I/L. For first-generation NNRTIs, the substitutions K103N, Y181C, G190A/S/E were chosen as herald of RAMs for this class [Jakobsen et al., 2010]. Prevalence of any NNRTIs-related RAMs was compared to any RPV-related (and to the main substitutions , K101E and E138K). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rilpivirine (RPV) is a novel NNRTI with a mutational pattern different from first-generation drugs of the same class: 16 resistance-associated mutations (RAM) are listed, but the combination E138K + M184I seems to be the most important. Aims of the present study were to evaluate the prevalence of these RAMs in Italian HIV-1 infected patients and to assess if previous drug history could represent a risk to develop RPV-related RAMs. The analysis was performed using the ARCA database, which contains data on resistance and therapy from subjects throughout Italy. Prevalence of RPV-associated and first-generation NNRTI-associated RAMs was evaluated. Linear regression model, odds ratio and 95% Confidence Interval were used to assess factors associated with the development of RPV RAMs, substitutions at position 184 and their combinations. A total of 8,067 tests were selected within the database. In Italian HIV-positive HAART-naïve patients, prevalence of the main RAMs for RPV is low except for E138A (present in 5.1% of subjects). The combination E138K + M184I is absent in both naïve and experienced subjects. A previous exposure to NVP might increase the risk to develop RPV-associated RAMs. TDF, EFV, and possibly FTC may predispose to the selection for M184I. Among Italian patients the susceptibility to RPV is widespread since some severe substitutions (e.g., E138K are rare), whereas issues exist for others (i.e., E138A, Y181C) which are more frequent. Appropriate use of RPV within a therapeutic sequencing might be controversial. J. Med. Virol. 9999: XX–XX, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Medical Virology 09/2014; 86(9). DOI:10.1002/jmv.23978 · 2.22 Impact Factor
  • Source
    • "Clinical studies aiming at validation of these sensitive methodologies show inconsistent results. Some studies failed to show a significant correlation between the presence of minority variants and subsequent virologic failure (Balduin et al., 2009; Jakobsen et al., 2010; Metzner et al., 2011; Peuchant et al., 2008) while others reported an overt correlation (Geretti et al., 2009; Goodman et al., 2011; Halvas et al., 2010; Johnson et al., 2008; Paredes et al., 2010; Simen et al., 2009). A recent systematic analysis of pooled clinical "
    [Show abstract] [Hide abstract]
    ABSTRACT: There are conflicting data on the impact of low frequency HIV-1 drug-resistant mutants on the response of first-line highly active antiretroviral therapy (HAART), more specifically containing a NNRTI. As population sequencing does not detect resistant viruses representing less than 15-25% of the viral population, more sensitive techniques have been developed but still need clinical validation. We evaluated ultra-deep sequencing (UDPS), recently more available and affordable, as a tool for the detection of HIV-1 minority species carrying drug resistant mutation (DRM) in a clinical setting. A retrospective analysis of the reverse transcriptase (RT) gene of plasma HIV-1 from 70 patients starting a NNRTI based regimen was performed. Minority populations were defined as representing > 1% and < 20% of the total viral population. Using UDPS, we could not confirm an association between the presence of low minority variants harbouring RT mutations at the start of therapy and primary or secondary therapeutic failure.
    Virology 04/2012; 426(1):7-11. DOI:10.1016/j.virol.2012.01.002 · 3.28 Impact Factor
  • Source
    • "Characteristic Peuchant 15 2008 Simen 14 2009 Balduin 16 2009 Jakobsen 17 2010 Metzner 18 2010 Goodman 19 2011 Paredes 20 2010 Johnson 21 2008 Geretti 22 2009 Metzner 23 2009 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Presence of low-frequency, or minority, human immunodeficiency virus type 1 (HIV-1) drug resistance mutations may adversely affect response to antiretroviral treatment (ART), but evidence regarding the effects of such mutations on the effectiveness of first-line ART is conflicting. To evaluate the association of preexisting drug-resistant HIV-1 minority variants with risk of first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral virologic failure. Systematic review of published and unpublished studies in PubMed (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. 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 drug resistance testing. 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. Individual data from 10 studies and 985 participants were available for the primary analysis. Low-frequency drug resistance mutations were detected in 187 participants, including 117 of 808 patients in the cohort studies. Low-frequency HIV-1 drug resistance mutations were associated with an increased risk of virologic failure (hazard ratio (HR], 2.3 [95% confidence interval {CI}, 1.7-3.3]; P < .001) after controlling for medication adherence, race/ethnicity, baseline CD4 cell count, and plasma HIV-1 RNA levels. 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 < .001). Among participants from the cohort studies, 35% of those with detectable minority variants experienced virologic failure compared with 15% of those without minority variants. The presence of minority variants was associated with 2.5 to 3 times the risk of virologic failure at either 95% or greater or less than 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. In a pooled analysis, low-frequency HIV-1 drug resistance mutations, particularly involving NNRTI resistance, were significantly associated with a dose-dependent increased risk of virologic failure with first-line ART.
    JAMA The Journal of the American Medical Association 04/2011; 305(13):1327-35. DOI:10.1001/jama.2011.375 · 30.39 Impact Factor
Show more

Martin R Jakobsen