The protease inhibitors, or PIs, work at a later stage in the HIV lifecycle than the NRTIs and NNRTIs. Once HIV's genetic material has been changed from RNA to DNA and is integrated into the DNA in the cell's nucleus, the cell produces a long chain of genetic material (proteins and enzymes). HIV's protease
enzyme acts like a pair of scissors, cutting the chain into smaller pieces which then come together to form new copies of the virus.
Protease inhibitors attach to the protease enzyme and keep it from cutting the long chain of proteins and enzymes into smaller pieces -- they block the scissors. HIV is unable to package itself into new infectious virus. When a PI is combined with other antiretrovirals -- usually two NRTIs -- the rate of HIV replication can be slowed down dramatically.
To varying degrees, PIs have been associated with certain long-term side effects, including increased blood sugar levels, insulin resistance, elevated cholesterol and triglyceride levels, osteonecrosis (death of bone tissue), and osteoporosis (a decrease in bone mineral density). Some of these conditions may increase a person's risk of heart disease, diabetes, and bone fractures. PIs have also been linked to various types of fat redistribution, which may be part of a larger syndrome involving changes in people's metabolism as a result of HIV disease, antiretrovirals used to treat HIV (not only the PIs), or both.
PIs have considerable drug interactions -- between each other, with non-nucleosides, and with many drugs used to treat other conditions. For example, each of the PIs interacts with the anti-tuberculosis drug rifampin, Viagra (sildenafil), St. John's wort, and a long list of other drugs. Be sure to talk to your healthcare provider about other medications you're taking, including over-the-counter treatments, herbs, and supplements.
Complete resistance to some of the PIs can develop as a result of just one mutation (change) in HIV's protease enzyme, such as the D30N mutation for Viracept
(nelfinavir) or the I50V mutation for Agenerase
(amprenavir). But with most of the PIs, it takes several mutations for complete resistance to develop. Partial or complete resistance to one PI can cause partial or complete cross-resistance to other PIs.
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