Highly active antiretroviral therapy has significantly improved HIV-related morbidity and mortality, and nucleoside reverse transcriptase inhibitors remain an essential component of treatment. However, the emergence of HIV-1 mutated strains that are resistant to one or more antiretroviral drugs is a leading cause of treatment failure among patients living with HIV/AIDS. These resistant strains may often suffer from a replication disadvantage in comparison with wild-type viruses when grown in the absence of drug pressure and a potential benefit in this regard has been shown for lamivudine-resistant viruses that contain a M184V mutation in reverse transcriptase, as well as for several other drug-resistant viral variants. Interactions between different mutations may complicate the understanding of HIV drug resistance with regard to the likelihood of therapeutic success.