Given the specificity of the target of these drugs there is the risk, as in antibiotics, of the development of drug-resistant mutated viruses. To reduce this risk it is common to use several different drugs together that are each aimed at different targets.
Protease inhibitors were the second class of antiretroviral drugs developed. The first members of this class, saquinavir (Hoffman-La Roche) and ritonovir (Abbott), were approved in late 1995-1996. Within 2 years, annual deaths from AIDS in the United States fell from over 50,000 to approximately 18,000  Prior to this the annual death rate had been increasing by approximately 20% each year.
The FDA approved it April 15, 1999, making it the sixteenth FDA-approved antiretroviral. It was the first protease inhibitor approved for twice-a-day dosing instead of needing to be taken every eight hours. The convenient dosing came at a price, as the dose required is 1,200 mg, delivered in eight very large gel capsules. Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir.
The FDA approved it on June 20, 2003. Atazanavir was the first PI approved for once-daily dosing. It appears to be less likely to cause lipodystrophy and elevated cholesterol as side effects. It may also not be cross-resistant with other PIs.
Is a prodrug of amprenavir. The FDA approved it October 20, 2003. The human body metabolizes fosamprenavir in order to form amprenavir, which is the active ingredient. That metabolization increases the duration that amprenavir is available, making fosamprenavir a slow-release version of amprenavir and thus reduces the number of pills required versus standard amprenavir.
It was approved by the Food and Drug Administration (FDA) on June 23, 2006. Prezista is an OARAC recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents. Several ongoing phase III trials are showing a high efficiency for the PREZISTA/rtv combination being superior to the lopinavir/rtv combination for first-line therapy. Darunavir is the first drug in a long time that didn't come with a price increase. It leapfrogged two other approved drugs of its type, and is matching the price of a third.
Researchers are investigating whether protease inhibitors could possibly be used to treat cancer. For example, nelfinavir and atazanavir are able to kill tumor cells in culture (in a Petri dish). This effect has not yet been examined in humans; but studies in laboratory mice have shown that nelfinavir is able to suppress the growth of tumors in these animals, which represents a promising lead towards testing this drug in humans as well.
^Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, November 3, 2008, Developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC). full guidelines.
^Madruga JV, Berger D, McMurchie M et al. (Jul 2007). "Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial". Lancet370 (9581): 49–58. doi:10.1016/S0140-6736(07)61049-6. PMID17617272.
^Dunn LA, Andrews KT, McCarthy JS et al. (2007). "The activity of protease inhibitors against Giardia duodenalis and metronidazole-resistant Trichomonas vaginalis". Int. J. Antimicrob. Agents29 (1): 98–102. doi:10.1016/j.ijantimicag.2006.08.026. PMID17137752.