Low-Frequency K103N Strengthens the Impact of Transmitted Drug Resistance on Virologic Responses to First-Line Efavirenz or Nevirapine-Based Highly Active Antiretroviral Therapy

Department of Virology, Royal Free Hampstead NHS Trust, London, UK.
JAIDS Journal of Acquired Immune Deficiency Syndromes (Impact Factor: 4.56). 09/2009; 52(5):569-73. DOI: 10.1097/QAI.0b013e3181ba11e8
Source: PubMed


There are conflicting data on the impact of low-frequency transmitted drug-resistant mutants on responses to first-line highly active antiretroviral therapy (HAART).
Patients started nevirapine or efavirenz with two or more nucleoside/nucleotide reverse transcriptase inhibitors in 1998-2007 without a prior resistance test at a median 1.0 (interquartile range, 0.0-3.4) year after diagnosis and with a median 218 (interquartile range, 131-296) CD4 cells/mm3, and had at least 24 weeks of follow up. Pre-HAART plasma samples were tested retrospectively by bulk genotyping and sensitive real-time polymerase chain reaction targeting reverse transcriptase K65R, K103N, Y181C, M184V, and G190A (interpretative cutoff 0.3%-0.9%).
Among 93 patients, seven of 18 who experienced virologic failure and zero of 75 who maintained virologic suppression showed pre-HAART resistance, including three with high-frequency mutations detectable by bulk genotyping (two K103N, one G190A) and four with low-frequency K103N detectable only by polymerase chain reaction. Detection of either bulk (P = 0.006) or low-frequency (P = 0.001) resistance was significantly associated with the odds of virologic failure; combining the two markedly increased the strength of the association (P < 0.0001). At failure, the pre-HAART mutations were detected by bulk genotyping in five of seven patients alongside additional reverse transcriptase mutations.
Low-frequency K103N mutants were as prevalent as bulk-detectable variants before starting HAART. Both high- and low-frequency mutants were significantly associated with virologic failure.

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    • "The median time course from diagnosis to the start of HAART was 1,2 (IQR 0,3 – 3,8) year, with a median CD4 count of 237 (IQR, 188–316) cells/mm3 at therapy start. Virologic failure was defined as primary when patients did not achieve a viral load (VL) below 50 copies/mL within 24 weeks of starting HAART and secondary when patients achieved a VL below 50 copies/mL within 24 weeks but experienced confirmed virologic rebound within 48 weeks according to Geretti et al. (2009). The pyrosequencing yielded an average of 5602 reads per site per patient sample. "
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    • "Studies have shown that pre-existing minority drug-resistant mutants increase the risk of virological failure to first-line antiretroviral therapy with non-nucleoside reverse transcriptase inhibitors (NNRTIs) [3], [4], [5], [6], [7]. Conversely, low-frequency drug-resistant variants do not affect virological outcomes of first-line therapy including drugs with high genetic barrier, like ritonavir-boosted protease inhibitors (PIr) [8]. "
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    • "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 "
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