Managing antiretroviral resistance

Abstract

Human immunodeficiency virus type 1 (HIV-1) was identified as causative agent of the acquired immune deficiency syndrome (AIDS) in 1983. Since then, 20 antiretroviral drugs inhibiting different steps of the viral life cycle have been approved for the treatment of HIV-infected individuals. Combinations of these drugs enable a sustained suppression of viral replication in the majority of treated subjects. Therapy failure frequently occurs with suboptimal drug concentrations promoting the development of drug-resistant viral strains. The increased capacity of a virus to replicate in the presence of antiretroviral drugs, based on mutations in the respective genes, can be detected by phenotypic or genotypic analysis. Retro- and prospective studies confirm that viral replication can be suppressed more effectively when antiretroviral therapy is adjusted to the individual resistance profile. Therefore, drug resistance testing is recommended for all cases of therapy failure; and for newly infected individuals as well, because current epidemiological data show a 10% risk for the transmission of drug-resistant viruses in this group. This review will focus on three aspects: (i) the development of drug resistance interpretation systems and the move towards a consensus, (ii) the impact of pharmacokinetics in drug applications and the design of new antiretrovirals, and (iii) the role of viral fitness in HIV-infected individuals harboring multidrug-resistant viruses. Thus, HIV infection has become a treatable chronic disease, which requires all our efforts to maintain the current truce, until a cure will eventually be found.