Induction therapy with protease-inhibitors modifies the effect of nevirapine resistance on virologic response to nevirapine-based HAART in children.
BACKGROUND
Nevirapine resistance after failed prophylaxis to prevent mother-to-child human immunodeficiency virus (HIV) transmission can compromise subsequent nevirapine-based highly active antiretroviral therapy (HAART).


METHODS
Nevirapine-exposed children who achieved virologic suppression with lopinavir/ritonavir-based induction HAART before switch to nevirapine-based HAART or who continued the lopinavir/ritonavir regimen were studied. Nevirapine-resistant HIV was quantified (≥ 1% frequency) in plasma before therapy and archived in peripheral blood mononuclear cells after induction HAART with ultradeep pyrosequencing. The primary endpoint was virologic failure (confirmed viremia ≥ 1000 copies/mL by 52 weeks) on nevirapine-based HAART, and Receiver operating characteristic analysis identified threshold levels of resistance associated with failure.


RESULTS
Nevirapine resistance mutations were detected in plasma at a median frequency of 25.6% in 41 (33%) of 124 children starting HAART at median 9 months of age. After a median nine months of induction HAART, nevirapine-resistant HIV remained archived in cells in 59 (61%) of 96 children (median 13.6% of cells). The threshold frequency of nevirapine resistance in plasma most predictive of virologic failure on nevirapine-based HAART was 25%. Children maintaining resistance before therapy at or above this threshold frequency had a 3.5 fold higher risk of failure (95% confidence interval, 1.1-10.8) than children without detectable plasma resistance. In contrast, virologic failure was not independently associated with age, resistance in plasma below 25% frequencies, or archived in cells.


CONCLUSIONS
Virologic suppression with lopinavir/ritonavir-based HAART in nevirapine-exposed children raises the threshold level of resistance at which reuse of nevirapine-based therapy is compromised. Standard genotyping may allow identification of children likely to benefit from an induction-switch approach.
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Anitha
A
Moorthy
Louise
L
Kuhn
Ashraf
A
Coovadia
Tammy
T
Meyers
Renate
R
Strehlau
Gayle
G
Sherman
Wei-Yann
WY
Tsai
Ya Hui
YH
Chen
Elaine J
EJ
Abrams
Deborah
D
Persaud
D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D002675:Child, Preschool; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D006678:HIV / Q000187:drug effects / Q000302:isolation & purification*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage*; D006801:Humans; D007223:Infant; D008297:Male; D019829:Nevirapine / Q000008:administration & dosage*; D012367:RNA, Viral / Q000235:genetics; D016896:Treatment Outcome; D019562:Viral Load; D014766:Viremia
D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D019829:Nevirapine
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