Abstract
BackgroundNon-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants have been shown to emerge after interruption of suppressive NNRTI-based antiretroviral therapy (ART) using routine testing. The aim of this study was to quantify the risk of resistance by sensitive testing and correlate the detection of resistance with NNRTI concentrations after treatment interruption and virologic responses after treatment resumption.MethodsResistance-associated mutations (RAMs) and NNRTI concentrations were studied in plasma from 132 patients who interrupted suppressive ART within SMART. RAMs were detected by Sanger sequencing, allele-specific PCR, and ultra-deep sequencing. NNRTI concentrations were measured by sensitive high-performance liquid chromatography.ResultsFour weeks after NNRTI interruption, 19/31 (61.3%) and 34/39 (87.2%) patients showed measurable nevirapine (>0.25 ng/ml) or efavirenz (>5 ng/ml) concentrations, respectively. Median eight weeks after interruption, 22/131 (16.8%) patients showed ≥1 NNRTI-RAM, including eight patients with NNRTI-RAMs detected only by sensitive testing. The adjusted odds ratio (OR) of NNRTI-RAM detection was 7.62 (95% confidence interval [CI] 1.52, 38.30; p = 0.01) with nevirapine or efavirenz concentrations above vs. below the median measured in the study population. Staggered interruption, whereby nucleos(t)ide reverse transcriptase inhibitors (NRTIs) were continued for median nine days after NNRTI interruption, did not prevent NNRTI-RAMs, but increased detection of NRTI-RAMs (OR 4.25; 95% CI 1.02, 17.77; p = 0.03). After restarting NNRTI-based ART (n = 90), virologic suppression rates <400 copies/ml were 8/13 (61.5%) with NNRTI-RAMs, 7/11 (63.6%) with NRTI-RAMs only, and 51/59 (86.4%) without RAMs. The ORs of re-suppression were 0.18 (95% CI 0.03, 0.89) and 0.17 (95% CI 0.03, 1.15) for patients with NNRTI-RAMs or NRTI-RAMs only respectively vs. those without RAMs (p = 0.04).ConclusionsDetection of resistant mutants in the rebound viremia after interruption of efavirenz- or nevirapine-based ART affects outcomes once these drugs are restarted. Further studies are needed to determine RAM persistence in untreated patients and impact on newer NNRTIs.
Highlights
The SMART trial randomized HIV-1 infected patients with CD4 counts .350 cells/mm3 to take antiretroviral therapy (ART)either continuously or episodically, guided by the CD4 cell count [1]
We investigated the correlation between detection of nucleoside reverse transcriptase inhibitor (NNRTI) resistance and NNRTI concentrations after treatment interruption, and analyzed the findings in relation to virologic responses after resumption of NNRTI-based ART
These findings provide support to the notion that selection of NNRTI resistance can occur in patients experiencing slower NNRTI clearance after ART interruption
Summary
The SMART trial randomized HIV-1 infected patients with CD4 counts .350 cells/mm to take antiretroviral therapy (ART)either continuously or episodically, guided by the CD4 cell count [1]. In patients receiving ART with agents that have different elimination half-lives, simultaneous interruption of all drugs can lead to a period of inadvertent monotherapy, which can result in viral replication in the presence of a single drug, promoting selection of drug-resistant mutants. This is expected to be a problem especially with the non-nucleoside reverse transcriptase inhibitors (NNRTIs), as they show the longest plasma half-lives among available antiretrovirals [2]. Non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants have been shown to emerge after interruption of suppressive NNRTI-based antiretroviral therapy (ART) using routine testing. The aim of this study was to quantify the risk of resistance by sensitive testing and correlate the detection of resistance with NNRTI concentrations after treatment interruption and virologic responses after treatment resumption
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