Fig. 3.

Drug-dependent fitness landscape for the antiretroviral drug efavirenz derived using measured pharamacodynamic and pharmacokinetic parameters for wild-type and the K103N drug-resistant strain. Viral growth rate is positive only when R ₀ >1 (above gray dotted line). a Fitness of wild-type and resistant strains follow dose–response curves, resulting in a mutant selection window where resistant strains are selected. We compare a single mutant (K103N) to two hypothetical double mutants by adding either a second equivalent resistant mutation (further increases IC₅₀ and decreases slope) or a compensatory mutation (changes fitness cost only). b Drug concentrations decay over time according to drug half-life. c Relative fitnesses of wild-type and resistant strains consequently change over time as drug decays. d In the CSF, reduced drug penetration results in concentrations reduced to 0.5 %, allowing viral replication at higher systemic drug levels. e Assuming about 10 % of cells are susceptible to direct cell-to-cell transmission, which typically occurs with around 100 virions and is sustainable with a single virion. f Combining the effects of (d) and (e). g At the maximum clinical drug concentration (immediately following a dose), only the doubly resistant mutant can grow. h At intermediate concentrations, the single resistant mutant can grow, facilitating evolution of the compensated mutation or the untreatable doubly resistant mutant. i Without treatment, the wild type is favored. While the doubly resistant mutant can stepwise revert to wild type, the compensated mutant is less likely to do so due to the presence of a fitness valley at either of the intermediate single mutants. See Appendix for methods