Induction therapy with protease-inhibitors modifies the effect of nevirapine resistance on virologic response to nevirapine-based HAART in children

Abstract

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.

Figure 1.

Flow of participants through the study. HAART, highly active antiretroviral therapy; LPV/r, lopinavir/ritonavir; RT, reverse transcriptase. ^aIneligible for randomization because of nonsuppression, initiation of tuberculosis therapy, or increased levels of liver enzymes. ^bDiscontinued therapy because of study withdrawal, move from study area, or loss to follow-up.

Figure 2A.

Overall prevalence and median frequency of nevirapine-resistant human immunodeficiency virus (HIV) in the pretreatment plasma virus population in children initiating highly active antiretroviral therapy (HAART) between 2 and 24 months of age. Also shown are the prevalence of resistance for children <6 months, 6–12 months, and >12 months of age at start of HAART (Fisher exact test P = .007) and their associated frequencies of resistant HIV in the plasma virus population (Wilcoxon rank sum test P = .23). IQR, interquartile range.Figure 2B. Overall prevalence and median frequency of human immunodeficiency virus (HIV)–infected cells with nevirapine resistance mutations in peripheral blood mononuclear cells collected from children whose viral load was suppressed with lopinavir/ritonavir–based highly active antiretroviral therapy (HAART) for a median of 9 months. Also shown are the prevalence of resistance in cells for children <6 months, 6–12 months, and >12 months of age at start of HAART (Fisher exact test P = .19) and their associated frequencies of HIV-infected cells with resistance (Wilcoxon rank sum test P = .03). IQR, interquartile range; PBMCs, peripheral blood mononuclear cells.

Figure 3.

Kaplan-Meier estimates of virologic suppression (<1000 copies/mL at ≥2 visits) by 52 weeks after switch to nevirapine-based highly active antiretroviral therapy (HAART) for children in the study with resistance at ≥25% frequency (long-dashed line), <25% frequency (short-dashed line), and no detectable resistance in pretreatment plasma (<1%; solid line).