TY - JOUR
T1 - Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes
AU - Simen, Birgitte B.
AU - Simons, Jan Fredrik
AU - Hullsiek, Katherine Huppler
AU - Novak, Richard M.
AU - MacArthur, Rodger David
AU - Baxter, John D.
AU - Huang, Chunli
AU - Lubeski, Christine
AU - Turenchalk, Gregory S.
AU - Braverman, Michael S.
AU - Desany, Brian
AU - Rothberg, Jonathan M.
AU - Egholm, Michael
AU - Kozal, Michael J.
N1 - Funding Information:
Financial support: US Department of Veterans Affairs (Merit and Career Development Award to M.J.K.); National Institute of Allergy and Infectious Diseases (NIAID) (grant support for the Terry Beirn Community Programs for Clinical Research on AIDS [CPCRA] and the FIRST Study, 5U01AI042170–10 and 5U01AI046362–03); NIAID sponsored the FIRST study, and had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Ultra-deep sequencing was performed by 454 Life Sciences free of charge. a B.B.S. and J.F.S. contributed equally to the project.
PY - 2009/3/1
Y1 - 2009/3/1
N2 - Background. Minor (i.e., <20% prevalence) drug-resistant human immunodeficiency virus (HIV) variants may go undetected, yet be clinically important. Objectives. To compare the prevalence of drug-resistant variants detected with standard and ultra-deep sequencing (detection down to 1% prevalence) and to determine the impact of minor resistant variants on virologic failure (VF). Methods. The Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study (N = 1397) compared 3 initial antiretroviral therapy (ART) strategies. A random subset (n = 491) had baseline testing for drug-resistance mutations performed by use of standard sequencing methods. Ultra-deep sequencing was performed on samples that had sufficient viral content (N = 264). Proportional hazards models were used to compare rates of VF for those who did and did not have mutations identified. Results. Mutations were detected by standard and ultra-deep sequencing (in 14% and 28% of participants, respectively; P < .001). Among individuals who initiated treatment with an ART regimen that combined nucleoside and nonnucleoside reverse-transcriptase inhibitors (hereafter, "NNRTI strategy"), all individuals who had an NNRTI-resistance mutation identified by ultra-deep sequencing experienced VF. When these individuals were compared with individuals who initiated treatment with the NNRTI strategy but who had no NNRTI-resistance mutations, the risk of VF was higher for those who had an NNRTI-resistance mutation detected by both methods (hazard ratio [HR], 12.40 [95% confidence interval {CI}, 3.41-45.10]) and those who had mutation(s) detected only with ultra-deep sequencing (HR, 2.50 [95% CI, 1.17-5.36]). Conclusions. Ultra-deep sequencing identified a significantly larger proportion of HIV-infected, treatment-naive persons as harboring drug-resistant viral variants. Among participants who initiated treatment with the NNRTI strategy, the risk of VF was significantly greater for participants who had low- and high-prevalence NNRTI-resistant variants.
AB - Background. Minor (i.e., <20% prevalence) drug-resistant human immunodeficiency virus (HIV) variants may go undetected, yet be clinically important. Objectives. To compare the prevalence of drug-resistant variants detected with standard and ultra-deep sequencing (detection down to 1% prevalence) and to determine the impact of minor resistant variants on virologic failure (VF). Methods. The Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study (N = 1397) compared 3 initial antiretroviral therapy (ART) strategies. A random subset (n = 491) had baseline testing for drug-resistance mutations performed by use of standard sequencing methods. Ultra-deep sequencing was performed on samples that had sufficient viral content (N = 264). Proportional hazards models were used to compare rates of VF for those who did and did not have mutations identified. Results. Mutations were detected by standard and ultra-deep sequencing (in 14% and 28% of participants, respectively; P < .001). Among individuals who initiated treatment with an ART regimen that combined nucleoside and nonnucleoside reverse-transcriptase inhibitors (hereafter, "NNRTI strategy"), all individuals who had an NNRTI-resistance mutation identified by ultra-deep sequencing experienced VF. When these individuals were compared with individuals who initiated treatment with the NNRTI strategy but who had no NNRTI-resistance mutations, the risk of VF was higher for those who had an NNRTI-resistance mutation detected by both methods (hazard ratio [HR], 12.40 [95% confidence interval {CI}, 3.41-45.10]) and those who had mutation(s) detected only with ultra-deep sequencing (HR, 2.50 [95% CI, 1.17-5.36]). Conclusions. Ultra-deep sequencing identified a significantly larger proportion of HIV-infected, treatment-naive persons as harboring drug-resistant viral variants. Among participants who initiated treatment with the NNRTI strategy, the risk of VF was significantly greater for participants who had low- and high-prevalence NNRTI-resistant variants.
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U2 - 10.1086/596736
DO - 10.1086/596736
M3 - Article
C2 - 19210162
AN - SCOPUS:61849172898
SN - 0022-1899
VL - 199
SP - 693
EP - 701
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 5
ER -
