A combinatorial ledge: reverse transcriptase fidelity, total body viral burden, and the implications of multiple-drug HIV therapy for the evolution of antiviral resistance.

The chronicity, high mutation rates, and high circulating titers of HIV during the 'stable' phase of infection make rapid evolution of resistance mutations a key predictor of antiretroviral efficacy. Recent advances in measurement of viral RNA titers, turnover dynamics and the in vivo spectrum of resistance mutations allow realistic in vivo estimates of important kinetic parameters of within-patient evolution of viral resistance. First-order estimates of the frequency of viral genotypes necessary for resistance to many antiretroviral combination regimens indicate that many such genotypes pre-exist in patients prior to initiation of therapy. The combinatorial nature of observed multiply-resistant genotypes, however, along with current estimates of total-body viral load and viral turnover dynamics, imply a strikingly sharp transition associated with the change from two-drug to three-drug antiretroviral regimens: pre-existing resistance being near-certain in the first instance but highly unlikely in the second. This abrupt change, a 'combinatorial ledge', carries with it a number of important implications for the understanding and control of HIV infection and other potential targets of antiviral therapy.