Background: A discordant response to ART occurs when CD4 counts are stable or increased over time despite persistently detectable viral load (VL). For PI-based ART, this outcome is associated with CCR-5 co-receptor tropism, diminished viral replication capacity, and enhanced CD8 responses. Discordant responses to NNRTI-based ART are not well characterized.

Methods: 20 HIV+ patients on NNRTI-based ART were studied in 2 groups: Discordant (D-NN): VL >400 copies/mL sustained >1 year, CD4 >200 cells/mm³ with stable/increasing trend >1 year; Success (S-NN): VL <400 copies/mL, CD4 >200 cells/mm³ with increasing trend >1 year. Data from this cohort were compared to previously reported data from PI patients including discordant responders (D-PI), virologic success (S-PI), and treatment failures [increasing viral load, declining CD4 count (F-PI)]. All subjects were judged treatment adherent by history and resistance profile. Phenotypic/genotypic drug susceptibility (Phenosense HIV, GeneSeq HIV), and replication capacity (RC) (modified PhenoSense) were performed by Virologic, Inc. Immune assays included IFN-gamma EliSpot, T-cell subset quantification, and immune activation markers. Comparisons were made between groups by Wilcoxon Rank Sum or Chi-Square Test.

Results: Both D-NN and D-PI patients had high-grade phenotypic and genotypic resistance to their ART regimens, as did F-PI patients. Viral isolates (n=15) from all discordant patients (D-NN and D-PI) were R5 tropic (NSI); 7/9 failure patients had X4 tropic (SI) viruses (p=0.0007). While viruses from D-PI patients had diminished RC compared to F-PI patients, the RC of viruses from D-NN patients was significantly higher and similar to those failing PI-based ART (median RC values: D-NN=27% D-PI=12% F-PI=22%; D-NN vs. D-PI: p=0.002, D-NN vs. F-PI: p=0.6).  CD8 responses were significantly greater among discordant responders than either success or failure patients.  Immune activation was greatest in treatment failures, intermediate in discordant responders and lowest in treatment successes.

Conclusions: Patients with discordant CD4/VL responses differ from those failing ART by having diminished immune activation, enhanced HIV-specific CD8 responses and virus that is consistently R5-tropic. CD8 responses were greater in D-NN than in D-PI patients.  In contrast, PI-based ART affected replication capacity to a greater extent than NNRTI-based ART, perhaps reflecting differing barriers to resistance generation.