Pre-existing minority drug-resistant HIV-1 variants, adherence, and risk of antiretroviral treatment failure.
BACKGROUND
The clinical relevance of detecting minority drug-resistant human immunodeficiency virus type 1 (HIV-1) variants is uncertain.


METHODS
To determine the effect of pre-existing minority nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistant variants on the risk of virologic failure, we reanalyzed a case-cohort substudy of efavirenz recipients in AIDS Clinical Trials Group protocol A5095. Minority K103N or Y181C populations were determined by allele-specific polymerase chain reaction in subjects without NNRTI resistance by population sequencing. Weighted Cox proportional hazards models adjusted for recent treatment adherence estimated the relative risk of virologic failure in the presence of NNRTI-resistant minority variants.


RESULTS
The evaluable case-cohort sample included 195 subjects from the randomly selected subcohort (51 with virologic failure, 144 without virologic failure), plus 127 of the remaining subjects who experienced virologic failure. Presence of minority K103N or Y181C mutations, or both, was detected in 8 (4.4%), 54 (29.5%), and 11 (6%), respectively, of 183 evaluable subjects in the random subcohort. Detection of minority Y181C mutants was associated with an increased risk of virologic failure in the setting of recent treatment adherence (hazard ratio, 3.45 [95% confidence interval, 1.90-6.26]) but not in nonadherent subjects (hazard ratio, 1.39 [95% confidence interval, 0.58-3.29]). Of note, 70% of subjects with minority Y181C variants achieved long-term viral suppression.


CONCLUSIONS
In adherent patients, pre-existing minority Y181C mutants more than tripled the risk of virologic failure of first-line efavirenz-based antiretroviral therapy.


BACKGROUND
NCT00013520.
Paredes
Roger
R
Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA.
Lalama
Christina M
CM
Ribaudo
Heather J
HJ
Schackman
Bruce R
BR
Shikuma
Cecilia
C
Giguel
Francoise
F
Meyer
William A
WA
Johnson
Victoria A
VA
Fiscus
Susan A
SA
D'Aquila
Richard T
RT
Gulick
Roy M
RM
Kuritzkes
Daniel R
DR
D000328:Adult; D000480:Alkynes; D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D048588:Benzoxazines / Q000627:therapeutic use; D016022:Case-Control Studies; D015331:Cohort Studies; D003521:Cyclopropanes; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000145:classification* / Q000235:genetics* / Q000254:growth & development / Q000302:isolation & purification; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction / Q000379:methods; D016032:Randomized Controlled Trials as Topic; D017211:Treatment Failure
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C098320:efavirenz