Protease Inhibitors (HIV)

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Information about Protease Inhibitors (HIV)

The human immunodeficiency virus (HIV) protease inhibitors are a broad class of agents that are widely used in the therapy and prevention of HIV infection and the acquired immunodeficiency syndrome (AIDS).

Liver safety of Protease Inhibitors (HIV)

All of the currently available protease inhibitors have been associated with transient and usually asymptomatic elevations in serum aminotransferase levels, and several (atazanavir, indinavir) with mild-to-moderate elevations in indirect and total bilirubin concentration. The protease inhibitors are rare causes of clinically apparent, acute liver injury. In HBV or HCV coinfected patients, antiretroviral therapy with highly active antiretroviral therapy (HAART) including protease inhibitors may result in an exacerbation of the underlying chronic hepatitis B or C.

Mechanism of action of Protease Inhibitors (HIV)

The antiretroviral protease inhibitors act by binding to the catalytic site of the HIV protease, thereby preventing the cleavage of viral polyprotein precursors into mature, functional proteins that are necessary for viral replication. Most of these agents were developed by rational drug design based upon chemical structures that would interact with the catalytic site of the HIV protease, based upon x-ray crystallographic studies defining the three-dimensional molecular structure of the protease. For these reasons, the protease inhibitors are heterogeneous molecules with little structural similarity, most of which are peptide-like and resemble the short peptide that is cleaved by the viral protease (usually the N terminal side of the middle proline residue is phenylalanine-proline-proline).

FDA approval information for Protease Inhibitors (HIV)

The initial HIV protease approved for use in the United States was ritonavir (1996), followed in short order by indinavir (1996), nelfinavir (1997), saquinavir (1997), amprenavir (1999), lopinavir/ritonavir (2000), atazanavir (2003), fosamprenavir (2003), tipranavir (2005), and darunivir (2006). The potencies of these agents are similar and the major reason for using one or the other relates to pharmacokinetics (whether they are taken once vs multiple times daily), tolerance and presence of antiviral resistance.

Metabolism of Protease Inhibitors (HIV)

Most of the HIV protease inhibitors are metabolized by the liver, via the cytochrome P450 drug metabolizing enzymes. Importantly, all of the approved HIV protease inhibitors have the potential for significant drug-drug interactions because of their potential in inhibiting drug metabolizing enzymes, most commonly CYP 3A4. Ritonavir is the most potent CYP 3A4 inhibitor and, for this reason, is often combined in low doses (100 to 200 mg daily) with other protease inhibitors to produce a "booster" effect, increasing the plasma levels and half-life of the protease inhibitor without significantly increasing side effects. Cobicistat is a more recently introduced pharmacological enhancer which has inhibitory activity against several drug metabolizing enzymes besides CYP 3A4, including CYP 2D6 and the P-glycoprotein transporter, which makes it a potent means of increasing drug levels of agents metabolized by the cytochrome P450 system. Several fixed combinations of cobicistat with antiretroviral agents have been approved for use in the United States, including combinations with atazanavir (Evotaz), elvitegravir (Genvoya and Stribild), and darunavir (Prezcobix). Cobicistat is also available as a separate oral tablet of 150 mg (Tybos).

Resistance to Protease Inhibitors (HIV)

As with other antiretroviral agents, therapy with the protease inhibitors is limited by the development of antiviral resistance. For this reason, the protease inhibitors are given in combination with other antiretroviral agents, belonging to other drug classes, such as the nucleoside analogues, the nonnucleoside reverse transcriptase inhibitors and the miscellaneous agents. Introduction of the HIV protease inhibitors into clinical practice was followed by a dramatic increase in survival in HIV-infected populations, a major accomplishment towards the goal of decreasing the burden of HIV infection.

Liver safety of Protease Inhibitors (HIV)

The protease inhibitors are associated with four main forms of hepatotoxicity.

  1. First, are the mild-to-moderate elevations in serum aminotransferase and alkaline phosphatase levels that occur in a high proportion of patients taking protease inhibitor-containing antiretroviral regimens. Moderate-to-severe elevations in serum aminotransferase levels (above 5 times the upper limit of normal) are found in 2% to 18% of patients depending upon the agent, the frequency of monitoring and, most importantly, the presence of HBV or HCV coinfection. In patients with HIV without HCV or HBV infection ("mono-infection"), ALT and AST elevations are less frequent and levels above 5 times the upper limit of normal are reported in only 1% to 4% of recipients. These elevations are usually asymptomatic and self-limited and can resolve even with continuation of the medication. Outside of carefully monitored clinical trials, serum enzyme elevations are an uncommon reason for discontinuing therapy.
  2. A second liver related reaction to protease inihibitor therapy is hyperbilirubinemia without other evidence of liver injury. Therapy with two protease inhibitors–indinavir and atazanavir–is associated with elevations in unconjugated (indirect) and total serum bilirubin, and can cause clinically apparent jaundice in up to 10% of patients. These elevations are due to the inhibition of UDP glucuronyl transferase, the hepatic enzyme responsible for conjugation of bilirubin that is deficient in Gilbert syndrome. The hyperbilirubinemia is usually mild, averaging 0.9-1.5 mg/dL, but can be more marked in patients with Gilbert syndrome with increases of 2.5 mg/dL or more and clinical jaundice. The jaundice, however, is not indicative of hepatic injury. Nevertheless, the jaundice caused by these agents can be distressing to the patient and is an occasional reason for discontinuation.
  3. A third pattern of hepatotoxicity attributed to protease inhibitors is idiosyncratic, clinically apparent acute liver injury which has been reported with most agents but is decidedly rare. The few cases that have been reported have usually arisen within 1 to 12 weeks of starting therapy and the pattern of serum enzyme elevations has varied from hepatocellular to mixed to cholestatic. Signs of allergy or hypersensitivity (fever, rash, eosinophilia) can occur but are rare, as is autoantibody formation. The acute liver injury due to the protease inhibitors is usually self-limited, but it can be severe, and isolated cases of acute liver failure have been reported particularly in patients with preexisting, underlying liver disease.
  4. Finally, the fourth pattern of hepatotoxicity that occurs during protease inhibitor therapy is the exacerbation of an underlying chronic hepatitis B or C in coinfected individuals started on highly active antiretroviral therapy. The flare of hepatitis typically arises 2 to 12 months after starting therapy and is associated with a hepatocellular pattern of serum enzyme elevations and increases (followed by falls) in serum levels of hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA. These flares can be severe and fatal instances have been reported with many of the protease inhibitors.

The protease inhibitors have not been linked to lactic acidosis and acute fatty liver that are associated with several nucleoside analogue reverse transcriptase inhibitors such as stavudine, didanosine and zidovudine, and rare cases of acute hypersensitivity associated hepatotoxicity as occurs with nevirapine, efaverenz and abacavir. However, because the protease inhibitors are usually given in combination with several other antiretroviral medications, identification of the drug causing the hepatic injury can be difficult.

List of HIV protease inhibitors

Antiviral agents

Drugs for HIV Infection, in the Subclass Antiretroviral Agents

Drugs for Hepatitis B

Drugs for Hepatitis C

HCV NS5A Inhibitors

HCV NS5B (Polymerase) Inhibitors

HCV Protease Inhibitors

Combination Therapies

Drugs for Herpes Virus Infections (HSV, CMV, others)

Drugs for Influenza


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