Cross-resistance occurs when changes which cause resistance to one drug also cause resistance to another. This is important with the protease inhibitors because results show that resistance to one protease inhibitor may lead to cross-resistance with other protease inhibitors. Resistance to these drugs results in a very similar genotypic profile. Therefore someone who has developed resistance to one of these drugs will probably get no benefit from the other. Some people argue that these data support using saquinavir as a first protease inhibitor, since the risk of cross-resistance seems lower.
Most virologists strongly disagree.
Because saquinavir offers so little potency compared to the other protease inhibitors, its use does not warrant incurring any risk of cross-resistance. People who are resistant to saquinavir but not cross-resistant to indinavir or ritonavir will likely have reduced and shorter antiviral response with either drug, because saquinavir resistance requires at least one mutation which contributes to resistance to indinavir and ritonavir. Effectively, saquinavir resistance provides the first step toward resistance to the other protease inhibitors. Both drugs are currently in clinical studies. Laboratory studies suggest that there is a slight chance that nelfinavir will be cross-resistant to indinavir and ritonavir and a likely chance it will be cross resistant to saquinavir.