Hepatitis Treatment – Antiviral Drugs

by Pravin Shukle, MD

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    00:00 Let's move on to anti-hepatitis drugs.

    00:03 Now the anti-hepatitis drugs really the main say of therapy has been the interferon alpha agents.

    00:12 Now interferon alpha seems to work in viral penetration.

    00:16 And by inhibiting viral penetration, you are inhibiting probably the first or second step in viral replication.

    00:23 Anti-hepatitis B drugs are suppressive not curative.

    00:28 So we are not necessary curing the patient with hepatitis B.

    00:32 Anti-hepatitis C drugs are targeted for viral eradication.

    00:38 And in fact we have seen eradication in many patients.

    00:40 Let's talk about interferon alpha.

    00:45 Now interferon alpha is a cytokine.

    00:48 And it acts through the Janus kinases.

    00:51 So Janus was mythical Greek god, actually he was an Olympian, who had ten heads.

    01:00 And so we talk about Janus kinases as being those agents that seem to have a whole bunch of faces to them.

    01:08 Now the Janus kinase is phosphorylate STAT that stands for Signal Transducers and Activators of Transcription.

    01:16 So we call these JAK STAT receptors.

    01:20 And you can see the JAK portion down at the bottom.

    01:24 Now this causes an increase production of antiviral proteins.

    01:29 There is a specific activation of ribonuclease that degrades the viral messengerRNA when you activate these agents.

    01:37 This promotes the formation of natural killer cells that destroy infected liver cells.

    01:42 So that's why interferon alpha is such an important component of our immune system.

    01:48 Now, intramuscular injections, interferon alpha are usually how we administer this medication.

    01:55 The formulations vary from time and place.

    01:59 Now the absorption is relatively slow.

    02:02 It's given about two or three times per week.

    02:04 We do have something called pegylated forms that can be given once a week.

    02:09 Pegylated forms are first to encasing the inferon in certain types of almost mycells or liposomes.

    02:16 The elimination is through hydrolysis and proteolysis in the kidney.

    02:21 In terms of where we use these medications, they are most commonly used in chronic hepatitis B.

    02:27 But we have actually used in hepatitis C as well, usually acute hepatitis C.

    02:32 And we often combine it with ribavirin.

    02:35 In less common uses, we've used it in Kaposi's sarcoma in HIV patients.

    02:42 We've also used in papillomatosis and genital warts as well.

    02:46 Although that's actually much less commonly used.

    02:50 Now I have another category here called "Others" under anti-hepatitis drugs.

    02:55 It's actually quite a large category.

    02:57 Now we already spoke about interferon alpha.

    03:00 So I'm not going to go through it again.

    03:02 Now the other drugs that we use with hepatitis includes the DNA polymerase agents, the nucleoside inhibitors, the broad spectrum replication inhibitors and another set of drugs that I just call miscellaneous.

    03:18 Let's take a look at the DNA polymerase inhibitors.

    03:21 The prototypical drug of the DNA polymerase inhibitors is adefovir.

    03:28 It inhibits DNA polymerase of hepatitis B virus which results in chain termination of -- results in chain termination after incorporation of the virus into the cell.

    03:40 It has good oral bioavailability and it's unaffected by foods.

    03:45 You can do dose reduction in renal dysfunction because it is excreted by the kidney.

    03:50 It works quite well against viruses that are resistant to lamivudine which is another antiviral agent that I'll talk about.

    04:01 In fact let's talk about lamivudine now.

    04:03 It's a nucleoside inhibitor.

    04:06 And if you recall nucleoside inhibitors are working on that very important step of nucleic acid synthesis.

    04:12 It inhibits HIV reverse transcriptase.

    04:15 It's a very long acting agent in hepatitis B infected cells.

    04:20 Compared to say it's limited activity in HIV infected cells.

    04:25 It's often used as monotherapy in hepatitis B.

    04:30 It's relatively non-toxic and it causes a rapid suppression of hepatitis B viruses.

    04:38 Other agents that are active against hepatitis include the broad spectrum replication inhibitors.

    04:46 We also know this is ribavirin and it's actually quite a well known drug.

    04:51 It inhibits replication of a wide range of DNA and RNA.

    04:56 It effects influenza A and B.

    04:59 It effects parainfluenza and respiratory syncytial virus.

    05:04 It also is active against paramyxoviruses and hepatitis C as well as HIV.

    05:10 In terms of the mechanisms of action, we're not entirely sure how this particular drug works.

    05:17 We'll believe that it acts directly with guanine triphosphate to somehow cause an inhibition and capping of the viral messengerRNA.

    05:24 It also blocks RNA dependent polymerases which is why we use it so often.

    05:31 Now in terms of using this medication, remember that in order to improve it's absorption we actually want more acidity in the stomach.

    05:43 So we tend to tell patients to avoid antacids when you're taking ribavirin.

    05:48 It's eliminated by the kidney so we have to act dose reductions if there is renal failure.

    05:54 We often use it with interferon alpha in chronic hepatitis C.

    06:00 Remember that monotherapy with this particular agent is not very effective.

    06:05 In terms of toxicity, there's a dose dependent hemolytic anemia that's associated with this drug.

    06:11 And it is contraindicated in pregnancy.

    06:16 Miscellaneous drugs use to treat hepatitis patients include the following.

    06:23 Now we have nucleoside analogs that work against DNA polymerase.

    06:31 We have agents that are approved for lamivudine resistance.

    06:36 We have agents that inhibit RNA polymerase.

    06:40 This particular agent is quite active in hepatitis C virus.

    06:45 And we actually can achieve 95% curates when used in association with ribavirin.

    06:51 Boceprevir is also a protease inhibitor and it's used with ribavirin as well.

    About the Lecture

    The lecture Hepatitis Treatment – Antiviral Drugs by Pravin Shukle, MD is from the course Antimicrobial Pharmacology. It contains the following chapters:

    • INF-alpha
    • Nucleoside Inhibitors
    • Broad sprectrum Replication Inhibitors
    • Miscellaneous

    Included Quiz Questions

    1. Lamivudine
    2. Adefovir
    3. Entecavir
    4. Interferon
    5. Tenofovir
    1. It does not work against lamivudine-resistant strains of HBV.
    2. It has good oral bioavailability.
    3. It inhibits HBV DNA polymerase.
    4. Dose reduction is required in renal dysfunction.
    5. It results in chain termination after incorporation.
    1. Ribavirin
    2. Adefovir
    3. Entecavir
    4. Tenofovir
    5. Lamivudine
    1. Ribavirin
    2. Lamivudine
    3. Zidovudine
    4. Emtricitabine
    5. Tenofovir

    Author of lecture Hepatitis Treatment – Antiviral Drugs

     Pravin Shukle, MD

    Pravin Shukle, MD

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