Background:  Many HIV-infected children and adolescents receiving ART display sustained CD4 T cell reconstitution despite viral load rebound. Factors contributing to discordant viral and immune outcomes were evaluated in a cohort of children and adolescents with ongoing viral replication on ART and equivalent degrees of T cell reconstitution.

Methods:  A prospectively accrued population of 43 HIV-infected children and adolescents, (2 to 24 years) with viral load >4.0 log₁₀ copies/mL and CD4 T cells <25% were evaluated over 96 weeks following initiation of protease inhibitor containing ART. Subjects who did not improve CD4 T cell numbers switched to a new regimen at 24 weeks, those who showed CD4 T cell reconstitution continued on current therapy even if VL rebounded.

Results:  By 24 weeks of ART 37% subjects reconstituted CD4 counts (immune success, IS) and suppressed virus (viral success VS) while 12% were switched to new ART because of viral and immune failure (VF/IF). Discordant outcomes (VF/IS) occurred in 51%, falling into 2 distinct responses based on viral decay slopes. Post-therapy steady state VL declined significantly by >1.5 log₁₀ copies/mL (VF/IS_low) in 1 group but another group (59% of VFIS) had persistently high viral replication (VF/IS_high). Despite difference in viremia (median viral load log₁₀ 5.1, VF/IS_high; 3.5, VF/IS_low; p = 0.004) increase in CD4 T cells/µL did not differ among groups (324, VS/IS; 391, VF/IS_high; and 279, VF/IS_low; p = 0.93). Median CD4 CD45RA naive T cells/µL increased similarly, 268 in VS/IS; 206 in VF/IS_high; and 108 in VF/IS_low (p = 0.78). Mean TREC levels within T lymphocytes was 17,147, 21,807, and 9318 copies/10⁶ peripheral blood mononuclear cells (PBMC) in VSIS, VF/IS_high and VF/IS_low, respectively (p = 0.25). Significant post-therapy improvement in prevalence of HIV-1-associated illnesses was seen in VF/IS_high group despite levels of viremia that would predict disease progression (p = 0.049). Mean PR mutations at 24 weeks were 3.6 in VF/IS_high and 1.2 in VF/IS_low (p = 0.11). No particular mutation at the catalytic protease site or supplemental mutations were predictive of high or low replicating viruses.

Conclusions:  In patients with sustained immune reconstitution continuing therapy in spite of drug-resistant viruses can result in good long-term clinical outcomes. Improvement in naïve CD4 T cells and high TREC levels suggests that drug-resistant viruses may be attenuated, sparing T cell production in discordant patients.