Association between detection of HIV-1 DNA resistance mutations by a sensitive assay at initiation of antiretroviral therapy and virologic failure.
BACKGROUND
Antiretroviral therapy (ART) has become more available throughout the developing world during the past 5 years. The World Health Organization recommends nonnucleoside reverse-transcriptase inhibitor-based regimens as initial ART. However, their efficacy may be compromised by resistance mutations selected by single-dose nevirapine (sdNVP) used to prevent mother-to-child transmission of human immunodeficiency virus (HIV)-1. There is no simple and efficient method to detect such mutations at the initiation of ART.


METHODS
One hundred eighty-one women who were participating in a clinical trial to prevent mother-to-child transmission and who started NVP-ART after they had received sdNVP or a placebo were included in the study. One hundred copies of each patient's HIV-1 DNA were tested for NVP-resistance point-mutations (K103N, Y181C, and G190A) with a sensitive oligonucleotide ligation assay that was able to detect mutants even at low concentrations (> or = 5% of the viral population). Virologic failure was defined as confirmed plasma HIV-1 RNA >50 copies/mL after 6 to 18 months of NVP-ART.


RESULTS
At initiation of NVP-ART, resistance mutations were identified in 38 (26%) of 148 participants given sdNVP (K103N in 19 [13%], Y181C in 8 [5%], G190A in 28 [19%], and > or = 2 mutations in 15 [10%]), at a median 9.3 months after receipt of sdNVP. The risk of virologic failure was 0.62 (95% confidence interval [CI], 0.46-0.77) in women with > or = 1% resistance mutation, compared with a risk of 0.25 (95% CI, 0.17-0.35) in those without detectable resistance mutations (P < .001). Failure was independently associated with resistance, an interval of <6 months between sdNVP and NVP-ART initiation, and a viral load higher than the median at NVP-ART initiation.


CONCLUSIONS
Access to simple and inexpensive assays to detect low concentrations of NVP-resistant HIV-1 DNA before the initiation of ART could help improve the outcome of first-line ART.
Jourdain
Gonzague
G
Institut de Recherche pour le Développement, UMI 174-PHPT, Thailand. Gonzague.Jourdain@ird.fr
Wagner
Thor Andrew
TA
Ngo-Giang-Huong
Nicole
N
Sirirungsi
Wasna
W
Klinbuayaem
Virat
V
Fregonese
Federica
F
Nantasen
Issaren
I
Techapornroong
Malee
M
Halue
Guttiga
G
Nilmanat
Ampaipith
A
Wittayapraparat
Pakorn
P
Chalermpolprapa
Veeradet
V
Pathipvanich
Panita
P
Yuthavisuthi
Prapap
P
Frenkel
Lisa M
LM
Lallemant
Marc
M
D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D004279:DNA, Viral / Q000235:genetics*; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D022521:Ligase Chain Reaction / Q000379:methods; D008826:Microbial Sensitivity Tests / Q000379:methods; D020125:Mutation, Missense; D019829:Nevirapine / Q000627:therapeutic use; D017211:Treatment Failure
D019380:Anti-HIV Agents; D004279:DNA, Viral; D019829:Nevirapine