What are the possible ways of overcoming HIV resistance to protease inhibitors and which of those are routinely employed?
Dr. Jonathan Schapiro responds:
It is important to keep in mind that resistance to PIs is a continuum and not a yes or no phenomenon. As mutations accumulate in the protease gene, the virus obtains increasing loss of susceptibility to PIs. Depending on the specific mutations and how many have accumulated, the degree of resistance (or reduced susceptibility) to a certain PI will be determined. This is also a function of the degree of exposure to the drug. Higher drug levels can overcome certain degrees of resistance as demonstrated by lopinavir/ritonavir or other boosted PIs. I have included a graphic presentation of this approach below (see figures).
High degrees of resistance are not overcome since the levels of drug required for this are either too toxic or cannot be obtained. Therefore, depending on which mutations have accumulated and their number, resistance to PIs can be overcome either by switching to a different PI, or often switching to a PI used with ritonavir boosting. Moderate or high degrees of PI resistance often cannot be overcome and require use of other drug classes, although immunological (CD4 counts) and clinical benefit can often still be maintained by continuing PI use even when mutations are present and viral load is no longer undetectable. The mechanism for this appears to be reduced viral fitness as a result of the mutations.
