THE PROBLEM OF RESISTANCE

Highly Active Antiretroviral Therapy

During the initial years of treating the HIV/AIDS epidemic in the United States and other parts of the developed world where treatment was available, ART consisted of the use of one or two drugs, known as mono or dual therapy. By the mid-1990s, as additional drugs were developed for HIV, it became clear that other therapy regimens might be better. Highly active antiretroviral therapy (HAART), a regimen based on using at least three ARVs from a minimum of two classes in combination, was developed in the mid- to late 1990s following the introduction of additional classes of ARVs and the recognition that using more drugs in combination is more effective in restoring immune function, decreasing HIV burden, and preventing the emergence of drug resistance. The three main classes are nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). (A drug from a fourth, newer class was approved in the United States in 2003 but is not yet widely used clinically and is not discussed further in this report.) HAART is now the standard treatment recommended in the United States. Appendix B provides a more thorough discussion of HAART.

Overview of Resistance

Drug resistance can render treatment ineffective for individual patients and has implications for the treatment of whole populations should they receive a high burden of transmitted drug-resistant virus. Resistance to HIV drugs arises in the presence of incomplete suppression of viral replication in the face of the selective pressure of drug treatment. The resistance-conferring mutations accumulate during rapid, error-prone HIV replication. The longer viral replication continues in the presence of inadequate ART regimens (i.e., failure of drugs to completely suppress viral replication), the more resistance will emerge. Even with low levels of virus present (i.e., between 50 and 500 copies/ml), drug resistance can develop (Fischl, 1999; Hirsch et al., 1998, 2000, 2003; Richman et al., 2004). The emergence of drug-resistant virus is one factor that can contribute to the failure of ART (Deeks, 2003). The fact that drug-resistant HIV-1 viral variants can still replicate well contributes to the rapid evolution of HIV in the face of potent drug pressure.

Although most resistance mutations confer a functional virus, the mutations can produce a virus with less replicative capacity than its wild-type relative. In theory, new mutations that emerge over time may often but not completely compensate for this defect. The lower fitness (or infectivity) of



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