Resisting Resistance: Maximizing the Durability of Antiretroviral Therapy

In the past 3 years, a veritable explosion of data has yielded new insight into the biology of HIV infection and the pathogenesis of AIDS. It is now well known that HIV infection, even during its long asymptomatic phase, is characterized by high rates of viral replication and destruction of CD4+ cells, which ultimately lead to immune deficiency, AIDS-defining illnesses, and death. Consequently, inhibition of viral replication has assumed primary importance in the control of AIDS.

Simultaneously, a new class of potent antiviral drugs, HIV protease inhibitors, was introduced. Protease inhibitors have proven, for the first time, that potent, sustained suppression of HIV replication can be achieved in a clinical setting for at least 2 years [1, 2] and that progression to AIDS and death can be dramatically reduced [3-5]. For this and other reasons, the number of AIDS-related deaths declined in the United States in 1996, the first such decline in the history of AIDS [6]. Thus, there is reason to be cautiously optimistic that with appropriate therapies, HIV and AIDS may ultimately be controlled.

For anti-HIV drugs to have long-term benefits, however, they must be used in a way that will completely suppress viral replication. This is because HIV, like any other microorganism, develops resistance to even the most potent suppressive agents if it is allowed to replicate, even slowly, in the presence of those agents. Drug resistance evolves through the accumulation of replication errors (mutations) in the viral population and the preferential survival of the mutants best able to replicate in the presence of the drug. This replication sets the stage for new rounds of mutation and selection, increasing the level of drug resistance over time. Thus, the evolution of drug resistance is a strict Darwinian process, driven by viral replication, mutation, and selection [7, …