Virological and immunological response to antiretroviral therapy in HIV-1 infected children: genotypic and phenotypic assays in monitoring virological failure.
Children differ from adults in both natural history of HIV-1 infection and their response to anti-retroviral therapy (ART). ART appears to be less successful in children than in adults at reducing HIV-1 RNA to below the level of detection of current assays. Nonetheless, children receiving ART frequently experience rises in CD4 cell counts, even in the absence of full virological suppression in plasma (discordant response). This immune repopulation in the presence of viral replication may increase the risk of emergence of drug-resistant viral variants. While the rationale for resistance testing is to optimise therapy, particularly when drugs are being changed following virological failure, it should be pointed out that currently available genotypic and phenotypic assays fail to detect drug resistance in about one third of viremic ART-treated children. This cannot be fully explained by the limitation of assays in detecting minor variants; factors other than resistance might be involved in the failure of therapy. Reduced fitness of drug-resistant viral variants is also unlikely to fully explain the discordant response to therapy, since immunological recovery is often observed even in the absence of detectable drug resistance. Rather, restoration of thymic function and higher thymic output may play a critical role in sustaining peripheral CD4 cell increases despite the persistence of viral replication. Such immune recovery might also drive the evolution of the replicating viruses.