Figure 4. Heterogeneity in time or space can allow the spread of drug resistant viruses.

(A) Different drugs and their associated drug resistance mutations have differently shaped concentration response curves and corresponding mutant selection windows (MSW). Pictured here, drug A (light blue) has the smallest MSW, whereas drug C (dark blue) has the widest MSW. Drug B (red) has an intermediate MSW. (B) Variable MSWs also interact with drugs that have heterogeneous concentrations either in time (top) or space (bottom). Missed doses (due to incomplete adherence, plotted on top) can allow only drugs with long half-lives (here, Drug B) to remain present. This can create windows in time (pictured in C) which select resistance to only this longest half-life drug. If drug levels are allowed to decline sufficiently low, viral replication of non-resistant types can emerge as well. Drugs that do not reach all of the body (plotted on bottom) can create areas where single drug resistance mutations (pictured in C) can replicate. Areas where effectively no drugs reach can create a sanctuary where some viral replication of the wild-type (WT) virus can continue.