The Emergence and Epidemiology of Resistance in the Nucleoside-Experienced HIV-Infected Population

Abstract

HIV drug resistance remains one of the most important influences on long-term therapeutic prospects. Resistance and therapeutic failure arises out of the selection and preservation of randomly generated genomic mutations that confer a replicative advantage in the presence of one or more antiretrovirals. The primary correlate to the time to emergence of a drug-resistant HIV variant is the extent of residual replication under selecting drug pressure, emphasizing the importance of full virological suppression to long-term therapy. Further contributions to the time to emergence are the degree of selective pressure exerted by a given drug, whereby greater potency forces earlier selection of mutant strains in balance with the extent of residual replication, and the degree of reduced drug susceptibility afforded by a particular mutation. Once evolved, drug-resistant strains can persist indefinitely as minority viral populations or archived genomes in latently infected CD4 cells, despite long-term withdrawal of the selecting drugs, to re-emerge rapidly on rechallenge with those or any cross-resistant drug. Variable adherence to medication in the routine clinical setting has given rise to resistance mutations being observed in some 50–60% of those with detectable viral loads on therapy in countries where anti-retroviral therapy has been widely available. Nucleoside reverse transcriptase inhibitor-associated mutations form the majority of these, and the long and almost universal use of zidovudine and stavudine has led to mutations selected by these drugs being the most common observed, along with the primary lamivudine resistance mutation M184V. Transmission of drug-resistant HIV in cases of new infection has also been widely studied, and although the extent is considerably lower than that in the treated population (typically 4–10% outside certain geographic areas), early data suggest that it is rising over time as the infected source population becomes more therapy-experienced. Once again, mutations from zidovudine or, to a lesser extent, stavudine exposure form the majority of mutations observed in cases of primary transmission. These data are a cause for concern, and imply that, as things stand, the use of a drug resistance test may become as important to the design of an effective first-line highly active antiretroviral therapy regimen as they have become for selecting new drugs on therapeutic failure.