Protease Inhibitors

PROTEASE INHIBITORS

During the later stages of the HIV growth cycle, the gag and gag-pol gene products are translated into polyproteins, and thesebecome immature budding particles. The HIV protease is respon-sible for cleaving these precursor molecules to produce the final structural proteins of the mature virion core. By preventing post-translational cleavage of the Gag-Pol polyprotein, protease inhibi-tors (PIs) prevent the processing of viral proteins into functional conformations, resulting in the production of immature, nonin-fectious viral particles (Figure 49–4). Unlike the NRTIs, PIs do not need intracellular activation.

Specific genotypic alterations that confer phenotypic resistance are fairly common with these agents, thus contraindicating mono-therapy. Some of the most common mutations conferring broad resistance to PIs are substitutions at the 10, 46, 54, 82, 84, and 90 codons; the number of mutations may predict the level of phe-notypic resistance. The I50L substitution emerging during atazana-vir therapy has been associated with increased susceptibility to other PIs. Darunavir and tipranavir appear to have improved virologic activity in patients harboring HIV-1 resistant to other PIs.

A syndrome of redistribution and accumulation of body fat that results in central obesity, dorsocervical fat enlargement (buffalo hump), peripheral and facial wasting, breast enlargement, and a cushingoid appearance has been observed in patients receiv-ing antiretroviral therapy. These abnormalities may be particularly associated with the use of PIs, although the recently licensed atazanavir appears to be an exception . Concurrent increases in triglyceride and low-density lipoprotein levels, along with hyperglycemia and insulin resistance, have also been noted. The cause is not yet known.

Whether PI agents are associated with bone loss and osteoporosis after long-term use is controversial and under investigation. PIs have been associated with increased spontaneous bleeding in patients with hemophilia A or B; an increased risk of intracranial hemorrhage has been reported in patients receiving tipranavir with ritonavir.

The concurrent use of saquinavir and ritonavir has recently been found to be associated with QT and PR interval prolonga-tion, and is contraindicated. QT prolongation may result in life-threatening torsades de pointes arrhythmia.

All of the antiretroviral PIs are extensively metabolized by CYP3A4, with ritonavir having the most pronounced inhibitory effect and saquinavir the least. Some PI agents, such as amprenavir and ritonavir, are also inducers of specific CYP isoforms. As a result, there is enormous potential for drug-drug interactions with other antiretroviral agents and other commonly used medications(Tables 49–3 and 49–4). Expert resources about drug-drug inter-actions should be consulted, as dosage adjustments are frequently required and some combinations are contraindicated. It is note-worthy that the potent CYP3A4 inhibitory properties of ritonavir are used to clinical advantage by having it “boost” the levels of other PI agents when given in combination, thus acting as a phar-macokinetic enhancer rather than an antiretroviral agent. Ritonavir boosting increases drug exposure, thereby prolonging the drug’s half-life and allowing reduction in frequency; in addition, the genetic barrier to resistance is raised.

ATAZANAVIR

Atazanavir is an azapeptide PI with a pharmacokinetic profile that allows once-daily dosing. It should be taken with a light meal to enhance bioavailability. Atazanavir requires an acidic medium for absorption and exhibits pH-dependent aqueous solubility; there-fore, separation of ingestion from acid-reducing agents by at least 12 hours is recommended and concurrent proton pump inhibitors are contraindicated. Atazanavir is able to penetrate both the cerebro-spinal and seminal fluids. The plasma half-life is 6–7 hours, which increases to approximately 11 hours when co-administered with ritonavir. The primary route of elimination is biliary; atazanavir should not be given to patients with severe hepatic insufficiency.

Resistance to atazanavir has been associated with various known PI mutations as well as with the novel I50L substitution. Whereas some atazanavir resistance mutations have been associated in vitro with decreased susceptibility to other PIs, the I50L mutation has been associated with increased susceptibility to other PIs.

The most common adverse effects in patients receiving ataza-navir are diarrhea and nausea; vomiting, abdominal pain, head-ache, peripheral neuropathy, and skin rash may also occur. As with indinavir, indirect hyperbilirubinemia with overt jaundice may occur in approximately 10% of patients, owing to inhibition of the UGT1A1 glucuronidation enzyme. Elevation of hepatic enzymes has also been observed, usually in patients with underly-ing HBV or HCV co-infection. Nephrolithiasis has recently been described in association with atazanavir use. In contrast to the other PIs, atazanavir does not appear to be associated with dys-lipidemia, fat redistribution, or the metabolic syndrome. Atazanavir may be associated with prolongation of the electrocardiographic PR interval, which is usually inconsequential but may be exacer-bated by other causative agents such as calcium channel blockers and may result in AV block QT prolongation is another potential electrocardiographic effect of atazanavir but is rarely clinically significant.

As an inhibitor of CYP3A4 and CYP2C9, the potential for drug-drug interactions with atazanavir is great (Tables 49–3 and 49–4). Atazanavir AUC is reduced by up to 76% when combined with a proton pump inhibitor; thus, these combinations are to be avoided. In addition, co-administration of atazanavir with other drugs that inhibit UGT1A1, such as irinotecan, may increase its levels. Tenofovir and efavirenz should not be co-administered with atazanavir unless ritonavir is added to boost levels.

DARUNAVIR

Darunavir is licensed as a PI that must be co-administered with ritonavir. It was initially licensed for use in treatment-experienced patients only; thus there is less clinical experience with its use in treatment-naïve patients. Darunavir may be administered once daily in treatment-naïve patients.Symptomatic adverse effects of darunavir include diarrhea, nausea, headache, and rash. Laboratory abnormalities include dyslipidemia (though possibly less frequent than with other boosted PI regimens) and increases in amylase and hepatic transaminase levels. Liver toxicity, including severe hepatitis, has been reported in some patients taking darunavir; the risk of hepatotoxicity may be higher for persons with HBV, HCV, or other chronic liver disease.Darunavir contains a sulfonamide moiety and should be used cautiously in patients with sulfonamide allergy.Darunavir both inhibits and is metabolized by the CYP3A enzyme system, conferring many possible drug-drug interactions (Tables 49–3 and 49–4). In addition, the co-administered ritona-vir is a potent inhibitor of CYP3A and CYP2D6, and an inducer of other hepatic enzyme systems.

FOSAMPRENAVIR

Fosamprenavir is a prodrug of amprenavir that is rapidly hydro-lyzed by enzymes in the intestinal epithelium. Because of its sig-nificantly lower daily pill burden, fosamprenavir tablets have replaced amprenavir capsules for adults. Fosamprenavir is most often administered in combination with low-dose ritonavir.

Amprenavir is rapidly absorbed from the gastrointestinal tract, and its prodrug can be taken with or without food. However, high-fat meals decrease absorption and thus should be avoided. The plasma half-life is relatively long (7–11 hours). Amprenavir is metabolized in the liver by CYP3A4 and should be used with caution in the setting of hepatic insufficiency.

The most common adverse effects of fosamprenavir are headache, nausea, diarrhea, perioral paresthesias, depression, and rash. Up to 3% of patients may experience rashes (including Stevens-Johnson syndrome) severe enough to warrant drug discontinuation.

Amprenavir is both an inducer and an inhibitor of CYP3A4 and is contraindicated with numerous drugs (Tables 49–3 and 49–4). The oral solution, which contains propylene glycol, is con-traindicated in young children, pregnant women, patients with renal or hepatic failure, and those using metronidazole or disul-firam. Also, the oral solutions of amprenavir and ritonavir should not be co-administered because the propylene glycol in one and the ethanol in the other may compete for the same metabolic pathway, leading to accumulation of either. Because the oral solu-tion also contains vitamin E at several times the recommended daily dosage, supplemental vitamin E should be avoided. Amprenavir, a sulfonamide, is contraindicated in patients with a history of sulfa allergy. Lopinavir/ritonavir should not be co-administered with amprenavir owing to decreased amprenavir andaltered lopinavir exposures. An increased dosage of amprenavir is recommended when co-administered with efavirenz (with or without the addition of ritonavir to boost levels).

INDINAVIR

Indinavir requires an acidic environment for optimum solubility and therefore must be consumed on an empty stomach or with a small, low-fat, low-protein meal for maximal absorption (60–65%). The serum half-life is 1.5–2 hours, protein binding is approxi-mately 60%, and the drug has a high level of cerebrospinal fluid penetration (up to 76% of serum levels). Excretion is primarily fecal. An increase in AUC by 60% and in half-life to 2.8 hours in the setting of hepatic insufficiency necessitates dose reduction.

The most common adverse effects of indinavir are indirect hyperbilirubinemia and nephrolithiasis due to urinary crystalliza-tion of the drug. Nephrolithiasis can occur within days after initiat-ing therapy, with an estimated incidence of approximately 10%. Consumption of at least 48 ounces of water daily is important to maintain adequate hydration. Thrombocytopenia, elevations of serum aminotransferase levels, nausea, diarrhea, insomnia, dry throat, dry skin, and indirect hyperbilirubinemia have also been reported. Insulin resistance may be more common with indinavir than with the other PIs, occurring in 3–5% of patients. There have also been rare cases of acute hemolytic anemia. In rats, high doses of indinavir are associated with development of thyroid adenomas.

Since indinavir is an inhibitor of CYP3A4, numerous and complex drug interactions can occur (Tables 49–3 and 49–4). Combination with ritonavir (boosting) allows for twice-daily rather than thrice-daily dosing and eliminates the food restriction associated with use of indinavir. However, there is potential for an increase in nephrolithiasis with this combination compared with indinavir alone; thus, a high fluid intake (1.5–2 L/d) is advised.

LOPINAVIR

Lopinavir is currently formulated only in combination with ritonavir, which inhibits the CYP3A-mediated metabolism of lopinavir, thereby resulting in increased exposure to lopinavir. In addition to improved patient compliance due to reduced pill burden, lopinavir/ritonavir is generally well tolerated.Lopinavir should be taken with food to enhance bioavailability. The drug is highly protein bound (98–99%), and its half-life is 5–6 hours. Lopinavir is extensively metabolized by CYP3A, which is inhibited by ritonavir. Serum levels of lopinavir may be increased in patients with hepatic impairment.

The most common adverse effects of lopinavir are diarrhea, abdominal pain, nausea, vomiting, and asthenia. Elevations in serum cholesterol and triglycerides are common. Potential drug-drug inter-actions are extensive (Tables 49–3 and 49–4). Increased dosage of lopinavir/ritonavir is recommended when co-administered with efavirenz or nevirapine, which induce lopinavir metabolism. Concurrent use of fosamprenavir should be avoided owing to altered

DARUNAVIR

Darunavir is licensed as a PI that must be co-administered with ritonavir. It was initially licensed for use in treatment-experienced patients only; thus there is less clinical experience with its use in treatment-naïve patients. Darunavir may be administered once daily in treatment-naïve patients.Symptomatic adverse effects of darunavir include diarrhea, nausea, headache, and rash. Laboratory abnormalities include dyslipidemia (though possibly less frequent than with other boosted PI regimens) and increases in amylase and hepatic transaminase levels. Liver toxicity, including severe hepatitis, has been reported in some patients taking darunavir; the risk of hepatotoxicity may be higher for persons with HBV, HCV, or other chronic liver disease.

Darunavir contains a sulfonamide moiety and should be used cautiously in patients with sulfonamide allergy.

Darunavir both inhibits and is metabolized by the CYP3A enzyme system, conferring many possible drug-drug interactions (Tables 49–3 and 49–4). In addition, the co-administered ritona-vir is a potent inhibitor of CYP3A and CYP2D6, and an inducer of other hepatic enzyme systems.

FOSAMPRENAVIR

Fosamprenavir is a prodrug of amprenavir that is rapidly hydro-lyzed by enzymes in the intestinal epithelium. Because of its sig-nificantly lower daily pill burden, fosamprenavir tablets have replaced amprenavir capsules for adults. Fosamprenavir is most often administered in combination with low-dose ritonavir.

Amprenavir is rapidly absorbed from the gastrointestinal tract, and its prodrug can be taken with or without food. However, high-fat meals decrease absorption and thus should be avoided. The plasma half-life is relatively long (7–11 hours). Amprenavir is metabolized in the liver by CYP3A4 and should be used with caution in the setting of hepatic insufficiency.

The most common adverse effects of fosamprenavir are headache, nausea, diarrhea, perioral paresthesias, depression, and rash. Up to 3% of patients may experience rashes (including Stevens-Johnson syndrome) severe enough to warrant drug discontinuation.

Amprenavir is both an inducer and an inhibitor of CYP3A4 and is contraindicated with numerous drugs (Tables 49–3 and 49–4). The oral solution, which contains propylene glycol, is con-traindicated in young children, pregnant women, patients with renal or hepatic failure, and those using metronidazole or disul-firam. Also, the oral solutions of amprenavir and ritonavir should not be co-administered because the propylene glycol in one and the ethanol in the other may compete for the same metabolic pathway, leading to accumulation of either. Because the oral solu-tion also contains vitamin E at several times the recommended daily dosage, supplemental vitamin E should be avoided. Amprenavir, a sulfonamide, is contraindicated in patients with a history of sulfa allergy. Lopinavir/ritonavir should not be co-administered with amprenavir owing to decreased amprenavir andaltered lopinavir exposures. An increased dosage of amprenavir is recommended when co-administered with efavirenz (with or without the addition of ritonavir to boost levels).

INDINAVIR

Indinavir requires an acidic environment for optimum solubility and therefore must be consumed on an empty stomach or with a small, low-fat, low-protein meal for maximal absorption (60–65%). The serum half-life is 1.5–2 hours, protein binding is approxi-mately 60%, and the drug has a high level of cerebrospinal fluid penetration (up to 76% of serum levels). Excretion is primarily fecal. An increase in AUC by 60% and in half-life to 2.8 hours in the setting of hepatic insufficiency necessitates dose reduction.

The most common adverse effects of indinavir are indirect hyperbilirubinemia and nephrolithiasis due to urinary crystalliza-tion of the drug. Nephrolithiasis can occur within days after initiat-ing therapy, with an estimated incidence of approximately 10%. Consumption of at least 48 ounces of water daily is important to maintain adequate hydration. Thrombocytopenia, elevations of serum aminotransferase levels, nausea, diarrhea, insomnia, dry throat, dry skin, and indirect hyperbilirubinemia have also been reported. Insulin resistance may be more common with indinavir than with the other PIs, occurring in 3–5% of patients. There have also been rare cases of acute hemolytic anemia. In rats, high doses of indinavir are associated with development of thyroid adenomas.

Since indinavir is an inhibitor of CYP3A4, numerous and complex drug interactions can occur (Tables 49–3 and 49–4). Combination with ritonavir (boosting) allows for twice-daily rather than thrice-daily dosing and eliminates the food restriction associated with use of indinavir. However, there is potential for an increase in nephrolithiasis with this combination compared with indinavir alone; thus, a high fluid intake (1.5–2 L/d) is advised.

LOPINAVIR

Lopinavir is currently formulated only in combination with ritonavir, which inhibits the CYP3A-mediated metabolism of lopinavir, thereby resulting in increased exposure to lopinavir. In addition to improved patient compliance due to reduced pill burden, lopinavir/ritonavir is generally well tolerated.

Lopinavir should be taken with food to enhance bioavailability. The drug is highly protein bound (98–99%), and its half-life is 5–6 hours. Lopinavir is extensively metabolized by CYP3A, which is inhibited by ritonavir. Serum levels of lopinavir may be increased in patients with hepatic impairment.

The most common adverse effects of lopinavir are diarrhea, abdominal pain, nausea, vomiting, and asthenia. Elevations in serum cholesterol and triglycerides are common. Potential drug-drug inter-actions are extensive (Tables 49–3 and 49–4). Increased dosage of lopinavir/ritonavir is recommended when co-administered with efavirenz or nevirapine, which induce lopinavir metabolism. Concurrent use of fosamprenavir should be avoided owing to altered exposure to lopinavir with decreased levels of amprenavir. Also, con-comitant use of lopinavir/ritonavir and rifampin is contraindicated due to an increased risk for hepatotoxicity. Since the oral solution of lopinavir/ritonavir contains alcohol, concurrent disulfiram and metronidazole are contraindicated. There is no evidence of human teratogenicity of lopinavir/ritonavir; short-term safety in pregnant women has been demonstrated for mother and infant.

NELFINAVIR

Nelfinavir has high absorption in the fed state (70–80%), under-goes metabolism by CYP3A, and is excreted primarily in the feces. The plasma half-life in humans is 3.5–5 hours, and the drug is more than 98% protein-bound.

The most common adverse effects associated with nelfinavir are diarrhea and flatulence. Diarrhea often responds to anti-diarrheal medications but can be dose-limiting. Nelfinavir is an inhibitor of the CYP3A system, and multiple drug interactions may occur (Tables 49–3 and 49–4). An increased dosage of nelfi-navir is recommended when co-administered with rifabutin (with a decreased dose of rifabutin), whereas a decrease in saquinavir dose is suggested with concurrent nelfinavir. Co-administration with efavirenz should be avoided due to decreased nelfinavir levels. Nelfinavir has a favorable safety and pharmacokinetic profile for pregnant women compared with that of other PIs (Table 49–5); there is no evidence of human teratogenicity.

RITONAVIR

Ritonavir has a high bioavailability (about 75%) that increases with food. It is 98% protein-bound and has a serum half-life of 3–5 hours. Metabolism to an active metabolite occurs via the CYP3A and CYP2D6 isoforms; excretion is primarily in the feces. Caution is advised when administering the drug to persons with impaired hepatic function.

Potential adverse effects of ritonavir, particularly when adminis-tered at full dosage, are gastrointestinal disturbances, paresthesias (circumoral or peripheral), elevated serum aminotransferase levels, altered taste, headache, and elevations in serum creatine kinase. Nausea, vomiting, diarrhea, or abdominal pain typically occur during the first few weeks of therapy but may diminish over time or if the drug is taken with meals. Dose escalation over 1–2 weeks is recommended to decrease the dose-limiting side effects. Liver adenomas and carcinomas have been induced in male mice receiv-ing ritonavir; no similar effects have been observed to date in humans.

Ritonavir is a potent inhibitor of CYP3A4, resulting in many potential drug interactions (Tables 49–3 and 49–4). However, this characteristic has been used to great advantage when ritonavir is administered in low doses (100–200 mg twice daily) in combina-tion with any of the other PI agents, in that increased blood levels of the latter agents permit lower or less frequent dosing (or both) with greater tolerability as well as the potential for greater efficacy against resistant virus. Therapeutic levels of digoxin and theophyl-line should be monitored when co-administered with ritonavir

SAQUINAVIR

In its original formulation as a hard gel capsule (saquinavir-H; Invirase), oral saquinavir was poorly bioavailable (only about 4% after food). However, reformulation of saquinavir-H for once-daily dosing in combination with low-dose ritonavir has both improved antiviral efficacy and decreased gastrointestinal adverse effects.

Saquinavir should be taken within 2 hours after a fatty meal for enhanced absorption. Saquinavir is 97% protein-bound, and serum half-life is approximately 2 hours. Saquinavir has a large volume of distribution, but penetration into the cerebrospinal fluid is negligible. Excretion is primarily in the feces. Reported adverse effects include gastrointestinal discomfort (nausea, diarrhea, abdominal discomfort, dyspepsia) and rhinitis. When administered in combination with low-dose ritonavir, there appears to be less dyslipidemia or gastrointestinal toxicity than with some of the other boosted PI regimens. However, the concur-rent use of saquinavir and ritonavir is newly recognized to confer an increased risk of QT prolongation (with torsades de pointes arrhythmia) and PR interval prolongation.

Saquinavir is subject to extensive first-pass metabolism by CYP3A4 and functions as a CYP3A4 inhibitor as well as a sub-strate; thus, there are many potential drug-drug interactions (Tables 49–3 and 49–4). A decreased dose of saquinavir is recom-mended when co-administered with nelfinavir. Increased saquina-vir levels when co-administered with omeprazole necessitate close monitoring for toxicities. Digoxin levels may increase if co-administered with saquinavir and should therefore be monitored. Liver function tests should be monitored if saquinavir is co-administered with delavirdine or rifampin. There is no evidence of human teratogenicity from saquinavir; there is short-term safety data for both mother and infant.

TIPRANAVIR

Tipranavir is a newer PI indicated for use in treatment-experienced HIV-1-infected patients who harbor strains resistant to other PI agents. It is used in combination with ritonavir to achieve effective serum levels and is not approved for treatment-naïve patients.

Bioavailability is poor but is increased when taken with a high-fat meal. The drug is metabolized by the liver microsomal system and is contraindicated in patients with hepatic insufficiency. Tipranavir contains a sulfonamide moiety and should not be administered to patients with known sulfa allergy.

The most common adverse effects from tipranavir are diarrhea, nausea, vomiting, and abdominal pain. An urticarial or maculo-papular rash is more common in women and may be accompanied.by systemic symptoms or desquamation. Liver toxicity, including life-threatening hepatic decompensation, has been observed and is more common in patients with chronic HBV or HCV infection. Tipranavir should be discontinued in patients who have increased serum transaminase levels that are more than 10 times the upper limit of normal or more than 5 times normal in combination with increased serum bilirubin. Because of an increased risk for intra-cranial hemorrhage in patients receiving tipranavir/ritonavir, the drug should be avoided in patients with head trauma or bleeding diathesis. Other potential adverse effects include depression, eleva-tion in amylase, and decreased white blood cell count.

Tipranavir both inhibits and induces the CYP3A4 system. When used in combination with ritonavir, its net effect is inhibi-tion. Tipranavir also induces P-glycoprotein transporter and thus may alter the disposition of many other drugs (Table 49–4). Concurrent administration of tipranavir with fosamprenavir or saquinavir should be avoided owing to decreased blood levels of the latter drugs. Tipranavir/ritonavir may also decrease serum levels of valproic acid and omeprazole. Levels of lovastatin, simva-statin, atorvastatin, and rosuvastatin may be increased, increasing the risk for rhabdomyolysis and myopathy. Tipranavir contains a sulfonamide moiety and should be used cautiously in patients with sulfonamide allergy.