Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes.
BACKGROUND
Minor (i.e., <20% prevalence) drug-resistant human immunodeficiency virus (HIV) variants may go undetected, yet be clinically important.


OBJECTIVE
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.
Simen
Birgitte B
BB
454 Life Sciences, a Roche Company, Branford, Connecticut, USA.
Simons
Jan Fredrik
JF
Hullsiek
Katherine Huppler
KH
Novak
Richard M
RM
Macarthur
Rodger D
RD
Baxter
John D
JD
Huang
Chunli
C
Lubeski
Christine
C
Turenchalk
Gregory S
GS
Braverman
Michael S
MS
Desany
Brian
B
Rothberg
Jonathan M
JM
Egholm
Michael
M
Kozal
Michael J
MJ
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D002908:Chronic Disease; D018076:DNA, Complementary / Q000737:chemistry; D018450:Disease Progression; D024882:Drug Resistance, Viral; D005260:Female; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D012367:RNA, Viral / Q000235:genetics
D019380:Anti-HIV Agents; D018076:DNA, Complementary; D012367:RNA, Viral