Pharmacology
Summary
Protease inhibitors, often named with the suffix "-navir" like ritonavir, atazanavir, and indinavir, block the HIV protease and prevent it from cleaving polyprotein precursors necessary to assemble mature viruses. HIV proteases are encoded by the HIV pol gene, and if protease inhibitor resistance is developed, it will likely involve modification of the pol gene. As a result, protease inhibitors are not used as monotherapy, since resistance can form quickly.
Protease inhibitors are notable for metabolic side effects. Insulin resistance, which may lead to diabetes, dyslipidemias, and lipodystrophy are all possible adverse effects of these drugs. Notably, ritonavir is associated with CYP450 inhibition and is therefore used to boost the concentration of other PIs, though it is not used directly for treatment. Another very important interaction is with rifampin, a potent inducer of cytochrome P450 metabolism, which decreases serum protease inhibitor levels. This is notable in patients at risk for mycobacterial infection or exacerbation, and rifabutin is often substituted in these cases.
Lesson Outline
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FAQs
The pol gene in HIV codes for the production of several necessary enzymes, one of which is protease. Protease inhibitors act on these enzymes to prevent the virus from maturing and reproducing, thereby reducing viral load and slowing disease progression.
Protease inhibitors can have several side effects, including hyperglycemia due to insulin resistance, dyslipidemia, and lipodystrophy. Some patients may also experience nephrolithiasis, particularly with drugs like indinavir. Adequate hydration can help mitigate this risk.
Protease inhibitors may inhibit the cytochrome P-450 enzyme system, which can increase the concentration of other protease inhibitors in the body. In particular, ritonavir is used solely for this effect in order to "boost" the effect of other PIs like atazanavir; it is not used for treatment due to adverse effects at therapeutic doses.
Protease inhibitors act by inhibiting the function of the enzyme protease, which the virus needs to divide and mature. As a result, the virion - or viral particle - remains immature and cannot infect other cells to further propagate infection.
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