Antiviral Drugs: PROTEASE INHIBITORS USED TO TREAT HIV INFECTION
Inhibitors of HIV protease have significantly altered the course of this devastating viral disease. Within a year of their introduction in 1995, the number of deaths in the United States due to AIDS declined, although the trend appears to be leveling off.
These potent agents have several common features that characterize their pharmacology.
- Mechanism of action: All of the drugs in this group are reversible inhibitors of the HIV aspartyl protease (retropepsin), which is the viral enzyme responsible for cleavage of the viral polyprotein into a number of essential enzymes (RT, protease, and integrase) and several structural proteins. The inhibition prevents maturation of the viral particles and results in the production of noninfectious virions.
- Pharmacokinetics: High-fat meals substantially increase the bioavailability of some PIs, such as nelfinavir and saquinavir, whereas the bioavailability of indinavir is decreased, and others are essentially unaffected. The HIV PIs are all substantially bound to plasma proteins. All are substrates for the CYP3A4 isoenzyme, and individual PIs are also metabolized by other CYP450 isoenzymes. Metabolism is extensive, and very little of the PIs are excreted unchanged in urine. Dosage adjustments are unnecessary in renal impairment.
- Adverse effects: PIs commonly cause nausea, vomiting, and diarrhea. Disturbances in glucose and lipid metabolism also occur, including diabetes, hypertriglyceridemia, and hypercholesterolemia. Chronic administration results in fat redistribution, including loss of fat from the extremities, fat accumulation in the abdomen and the base of the neck (“buffalo hump”; and breast enlargement. These physical changes may indicate to others that an individual is HIV infected.
- Drug interactions: Drug interactions are a common problem for all PIs, because they are not only substrates but also potent inhibitors of CYP450 isoenzymes. Drug interactions are, therefore, quite common. Drugs that rely on metabolism for their termination of action may accumulate to toxic levels. Examples of potentially dangerous interactions from drugs that are contraindicated with PIs include rhabdomyolysis from simvastatin or lovastatin, excessive sedation from midazolam or triazolam, and respiratory depression from fentanyl. Other drug interactions that require dosage modification and cautious use include warfarin, sildenafil, and phenytoin. In addition, inducers of CYP450 isoenzymes may decrease PI plasma concentrations to suboptimal levels, contributing to treatment failures. Thus, drugs such as rifampin and St. John’s wort are also contraindicated with PIs.
- Resistance: Resistance occurs as an accumulation of stepwise mutations of the protease gene. Initial mutations result in decreased ability of the virus to replicate, but as the mutations accumulate, virions with high levels of resistance to the protease inhibitors emerge. Suboptimal concentrations of PI result in the more rapid appearance of resistant strains.
B. Ritonavir (RTV)
Ritonavir [ri-TOE-na-veer] is no longer used as a single PI but, instead, is used as a pharmacokinetic enhancer or “booster” of other PIs. Ritonavir is a potent inhibitor of CYP3A, and concomitant ritonavir administration at low doses increases the bioavailability of the second PI, often allowing for longer dosing intervals. The resulting higher Cmin levels of the “boosted” PI also help to prevent the development of resistance. Therefore, “boosted” PIs are preferred agents in the HIV treatment guidelines. Metabolism and biliary excretion are the primary methods of elimination. Ritonavir has a half-life of 3 to 5 hours. Because it is primarily an inhibitor of CYP450 isoenzymes, numerous drug interactions have been identified. Nausea, vomiting, diarrhea, headache, and circumoral paresthesias are among the more common adverse effects.
C. Saquinavir (SQV)
To maximize bioavailability, saquinavir [sa-KWIH-na-veer] is always given along with a low dose of ritonavir. High-fat meals also enhance absorption. Elimination of saquinavir is primarily by hepatic metabolism, followed by biliary excretion. Its half-life is 7 to 12 hours, requiring twice-daily dosing. The most common adverse effects of saquinavir include headache, fatigue, diarrhea, nausea, and other GI disturbances. Increased levels of hepatic aminotransferases have been noted, particularly in patients with concurrent hepatitis B or C infections.
D. Indinavir (IDV)
Indinavir [in-DIH-na-veer] is well absorbed orally and, of all the PIs, is the least protein bound. Acidic gastric conditions are necessary for absorption. Absorption is decreased when administered with meals, although a light, low-fat snack is permissible. Indinavir has the shortest half-life of the PIs, at 1.8 hours. Boosting with ritonavir overcomes this problem and also permits twice-daily dosing. Indinavir is extensively metabolized, and the metabolites are excreted in the feces and urine. The dosage should, therefore, be reduced in the presence of hepatic insufficiency. GI symptoms and headache are the predominant adverse effects. Indinavir characteristically causes nephrolithiasis and hyperbilirubinemia. Adequate hydration is important to reduce the incidence of kidney stone formation, and patients should drink at least 1.5 L of water per day. Fat redistribution is particularly troublesome with this drug.
E. Nelfinavir (NFV)
Nelfinavir [nel-FIN-a-veer] is well absorbed and does not require strict food or fluid conditions, although it is usually given with food. Nelfinavir undergoes metabolism by several CYP450 isoenzymes. It is the only PI that cannot be boosted by ritonavir, because it is not extensively metabolized by CYP3A. The half-life of nelfinavir is 5 hours. Diarrhea is the most common adverse effect and can be controlled with loperamide.
F. Fosamprenavir (FPV)
Fosamprenavir [fos-am-PREN-a-veer] is a prodrug that is metabolized to amprenavir following oral absorption. Its long plasma halflife permits twice-daily dosing. Coadministration of ritonavir increases the plasma levels of amprenavir and lowers the total daily dose. Fosamprenavir boosted with ritonavir is one of the alternative PIs according to the current HIV treatment guidelines. Nausea, vomiting, diarrhea, fatigue, paresthesias, and headache are common adverse effects.
G. Lopinavir (LPV/r)
Lopinavir [loe-PIN-a-veer] is an alternative PI, according to the HIV treatment guidelines. Lopinavir has very poor bioavailability, which is substantially enhanced by including a low-dose ritonavir booster in the formulation. GI adverse effects and hypertriglyceridemia are the most common adverse effects of lopinavir. Enzyme inducers as well as St. John’s wort should be avoided, because they lower the plasma concentrations of lopinavir. Because the oral solution contains alcohol, disulfiram or metronidazole administration can cause unpleasant reactions.
H. Atazanavir (ATV)
Atazanavir [ah-ta-ZA-na-veer] is a preferred PI. Atazanavir is well absorbed orally. It must be taken with food, because food increases absorption and bioavailability. The drug is highly protein bound and undergoes extensive metabolism by CYP3A4 isoenzymes. It is excreted primarily in bile. It has a half-life of about 7 hours, but it may be administered once daily. Atazanavir is a competitive inhibitor of glucuronyl transferase, and benign hyperbilirubinemia and jaundice are known adverse effects. In the heart, atazanavir prolongs the PR interval. Atazanavir exhibits a decreased risk of hyperlipidemia compared with other PIs. Unboosted atazanavir is contraindicated with concurrent use of proton pump inhibitors, and administration must be spaced apart from H2-blockers and antacids.
I. Tipranavir (TPV)
Tipranavir [ti-PRA-na-veer] is a nonpeptide PI that inhibits HIV protease in viruses that are resistant to the other PIs. Tipranavir is well absorbed when taken with food. The half-life is 6 hours, and it must be administered twice daily in combination with ritonavir. Adverse effects are similar to those of the other PIs, with the exception of severe and fatal hepatitis and rare cases of intracranial hemorrhage. Most patients experiencing these severe adverse effects have underlying comorbidities. Tipranavir is useful in “salvage” regimens in patients with multidrug resistance.
J. Darunavir (DRV)
Darunavir [da-RU-na-veer] is a preferred PI and is always given along with a low dose of ritonavir. Darunavir is approved for initial therapy in treatment-naïve HIV-infected patients, as well as for treatment- experienced patients with HIV that is resistant to other PIs. Darunavir must be taken with food to increase absorption. The elimination half-life is 15 hours when combined with ritonavir. Darunavir is extensively metabolized by the CYP3A enzymes and is also an inhibitor of the CYP3A4 isoenzyme. Adverse effects are similar to those of the other PIs. In addition, darunavir therapy has been associated with a rash.
Antiviral Drugs: ENTRY INHIBITORS USED TO TREAT HIV INFECTION
Enfuvirtide [en-FU-veer-tide] is a fusion inhibitor. For HIV to gain entry into the host cell, it must fuse its membrane with that of the host cell. This is accomplished by changes in the conformation of the viral transmembrane glycoprotein gp41, which occurs when HIV binds to the host cell surface. Enfuvirtide is a polypeptide that binds to gp41, preventing the conformational change. Enfuvirtide, in combination with other antiretroviral agents, is approved for therapy of treatment experienced patients with evidence of viral replication despite ongoing antiretroviral drug therapy. As a peptide, it must be given subcutaneously. Most of the adverse effects are related to the injection, including pain, erythema, induration, and nodules, which occur in almost all patients. Enfuvirtide must be reconstituted prior to administration.
Maraviroc [ma-RAV-i-rok] is another entry inhibitor. Because it is well absorbed orally, it is formulated as an oral tablet. Maraviroc blocks the CCR5 coreceptor that works together with gp41 to facilitate HIV entry through the membrane into the cell. HIV may express preference for either the CCR5 coreceptor or the CXCR4 coreceptor, or both (dual-tropic). Prior to use of maraviroc, a test to determine viral tropism is required to distinguish whether the strain of HIV virus uses the CCR5 coreceptor, the CXCR4 coreceptor, or is dual-tropic. Only strains of HIV that use CCR5 to gain access to the cell can be successfully treated with maraviroc. Maraviroc is metabolized by CYP450 liver enzymes, and the dose must be reduced when given with most PIs or strong CYP450 inhibitors. Conversely, it should be increased in patients receiving efavirenz, etravirine, or strong CYP450 inducers. Maraviroc is generally well tolerated.
Antiviral Drugs: INTEGRASE INHIBITORS USED TO TREAT HIV INFECTION
The integrase strand transfer inhibitors (INSTIs), often called integrase inhibitors, work by inhibiting the insertion of proviral DNA into the host cell genome. The active site of the integrase enzyme binds to the host cell DNA and includes two divalent metal cations that serve as chelation targets for the INSTIs. As a result, when an INSTI is present, the active site of the enzyme is occupied and the integration process is halted. The INSTIs are generally well tolerated, with nausea and diarrhea being the most commonly reported adverse effects. Importantly, INSTIs are subject to chelation interactions with antacids resulting in significant reductions in bioavailability. It is therefore recommended that INSTI doses are separated from antacids and other polyvalent cations by several hours. Resistance to INSTIs occurs with single-point mutations within the integrase gene. Cross-resistance between raltegravir and elvitegravir can occur, although dolutegravir has limited cross-resistance to other INSTIs.
In combination with other antiretroviral agents, raltegravir [ral-TEG-raveer] is approved for both initial therapy of treatment-naïve patients and treatment-experienced patients with evidence of viral replication despite ongoing antiretroviral drug therapy. Raltegravir has a half-life of approximately 9 hours and is dosed twice daily. The route of metabolism is UDP-glucuronosyltransferase (UGT)1A1-mediated glucuronidation and, therefore, drug interactions with CYP450 inducers, inhibitors, or substrates do not occur. Raltegravir is well tolerated, although serious adverse effects, such as elevated creatine kinase with muscle pain and rhabdomyolysis and possible depression with suicidal ideation, have been reported.
Elvitegravir [el-vi-TEG-ra-vir] is currently only available in a fixeddose combination single tablet containing tenofovir, emtricitabine, elvitegravir, and cobicistat. [Note: Cobicistat is a pharmacokinetic enhancer or booster drug used in combination treatments of HIV since it inhibits CYP3A enzymes.] The half-life of elvitegravir is 3 hours when administered alone, but increases to approximately 9 hours when boosted by cobicistat. Pharmacokinetic boosting of elvitegravir allows it to be dosed orally once daily with food. However, it can also lead to clinically significant drug interactions. Elvitegravir is highly bound to plasma proteins and is primarily metabolized in the liver via CYP3A, and to a lesser extent via UGT1A1/3 glucuronidation. It is mainly excreted in the feces. The most common adverse effect of elvitegravir is nausea, although cobicistat may also cause elevations in serum creatinine due to inhibition of tubular creatinine secretion. Cross-resistance between raltegravir and elvitegravir is high.
Dolutegravir [doe-loo-TEG-ra-vir] is rapidly absorbed following oral administration. Dolutegravir is highly protein bound and undergoes extensive hepatic metabolism. Metabolism primarily occurs through UGT1A1 with minor contributions from CYP3A4. Potent inducers and/or inhibitors of UGT1A1 and CYP3A4 can significantly alter dolutegravir concentrations. More than half the dose is eliminated unchanged in the feces; nearly a third is eliminated as metabolites in the urine. It is an inhibitor of the renal transport protein OCT2 and can result in mild, benign, and reversible elevation in serum creatinine. Dolutegravir can be given once daily without the use of a pharmacokinetic booster in patients without preexisting INSTI resistance. Twice-daily dosing is recommended for INSTI treatment-experienced patients or when strong UGT1A1 or CYP3A inducers are present. Depending on the specific genetic profile, some patients with raltegravir and elvitegravir resistance mutations maintain susceptibility to dolutegravir.[/sociallocker]