Nurs 723: Antiviral & Antiretroviral Drugs

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3 Categories of Chemotherapeutic Agents used for Viral Infections

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1) virucides
2) antivirals
3) immunomodulators

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Virucides

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*directly inactivate intact viruses
*agents that are most useful in mucocutaneous (relating to the skin & a mucous membrane) infections (ex: warts)
*may be most useful in preventing transmission
*ex: detergents, UV light, organic solvents

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Antivirals

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*inhibit viral replication at the cellular level
*inhibit virus specific events
*these agents often have a narrow therapeutic window: NOT effective in LATENT virus

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Immunomodulators

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*augment or modify the host response to infection
*replace deficient host immune responses or enhance endogenous cells
*ex: cytotoxic T-cells in CMV

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Sanctuary Sites

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*areas that viruses (like herpes & HIV) can latent in the body
*ex: cerebrospinal fluid (CSF)

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Possible Sites of Action in the Viral Replication Cycle

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1) Viral attachment to host cell
2) Cell entry & un-coating of the virus's RNA/DNA
3) Transcription: RNA to DNA
4) Translation: prevent virus from being encoded into our human DNA
5) Viral assembly: even if the virus has entered into the host DNA, prevents the virus from repackaging itself & creating new virions

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Spectrum of Action of Acyclovir (Zovirax)

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*Proven:
-Herpes Simplex Virus 1 / Herpes Simplex Virus 2
-Varicella-Zoster Virus
*Possible
-Epstein Barr Virus

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Acyclovir (Zovirax) MOA

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*guanosine analog-inhibits DNA synthesis
*looks like guanosine-will attach itself to the viral RNA
*when the reverse transcriptase begins transcribing (making viral DNA into human DNA) it terminates when it reaches this guanosine point in the chain

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Acyclovir (Zovirax) Formulation

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*Topical
*Oral
*IV

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Acyclovir (Zovirax) is the Gold Standard Treatment for which types of Infections

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*treatment of choice for visceral, disseminated (systemic), or central nervous system involvement of HSV infections

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Adverse Effects of Oral Acyclovir (Zovirax)

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*nausea
*diarrhea
*rash
*HA
*neutropenia

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Main Issue with PO Acyclovir (Zovirax)

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*high dose frequency: 400-800 mg, 5 times per day, for systemic infections
*poor patient compliance
*will consider PO Valacyclovir (Valtrex) or Famciclovir (Famvir) for this reason

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IV Acyclovir (Zovirax) is the gold standard for .....

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*HSV encephalitis
*or more severe systemic infections
*used until patient can take PO meds

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2 Major Adverse Effects with IV Acyclovir (Zovirax)

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1) Reversible Nephrotoxicity
2) Reversible Neurotoxicity
*Phlebitis

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Nephrotoxicity with IV Acyclovir (Zovirax)

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*causes crystallization in the renal tubules

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Management of Nephrotoxicity with IV Acyclovir (Zovirax)

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*DOSE ON IDEAL BODY WEIGHT* (esp. for obese pts.)
*Administer over 1 hour
*ADEQUATE HYDRATION* (maintenance IVFs or bolus of NS before & after dose)
*Adjust for renal dysfunction

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Symptoms of Neurotoxicity with IV Acyclovir (Zovirax)

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*encephalopathic changes
-somnolence
-hallucinations
-confusion
-seizures
-coma

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Spectrum of Activity of Ganciclovir (Cytovene)

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*Proven
-Cytomegalovirus
-Herpes Simplex Virus 1 / Herpes Simples Virus 2
-Varicella-Zoster Virus
-Epstein-Barr Virus
*Possible
-Herpes Virus 8
-Herpes Virus B

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Ganciclovir (Cytovene) versus Acyclovir (Zovirax)

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*Ganciclovir (Cytovene):
-structurally similar to Acyclovir (Zovirax) with the addition a hydroxymethyl group at the 3' position of the acyclovir side chain.
-10 times more potent against CMV & EBC than Acyclovir (Zovirax)
-broader spectrum of action than Acyclovir (Zovirax)

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True or False. Different viruses prefer different host cells.

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True

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Oral Bioavailability of Acyclovir

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*low bioavailability @ 15-21%
*bioavailability decreases with increasing doses

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Risk Factors for Nephrotoxicity with Acyclovir Administration

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1) Bolus Infusion
2) Dehydration
3) Pre-existing renal insufficiency
4) High dose

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Why does phlebitis occur with IV Acyclovir administration?

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*phlebitis occurs due to the alkaline solution of Acyclovir
*pH of 9-11

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Ganciclovir Formulations

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*Oral
*IV
*Intra-ocular

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Bioavailability of Oral Ganciclovir

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*low oral bioavailability of 5%
*increases only slightly with food to 10%

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MOA of Ganciclovir

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*inhibits viral DNA synthesis
*competitive inhibitor of deoxyguanosine triphosphate (dGTP)
*is NOT an absolute DNA-chain terminator

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Why is Ganciclovir superior to Acyclovir for the treatment of CMV?

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*Ganciclovir is converted to Ganciclovir monophosphate by a viral-encoded phosphotransferase produced in cells infected with CMV
*better substrate than Acyclovir for this phosphotransferase & the intracellular T1 & T2 is at least 12 hours as compared to 1-2 hours with Acyclovir

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Most Common Adverse Side Effect with Ganciclovir Administration

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*Bone Marrow Suppression = Reversible Pancytopenia*
*Profound Neutropenia & Thrombocytopenia
**This reaction is very unique to Ganciclovir; not seen with Acyclovir**

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Management of Pancytopenia Caused by Ganciclovir

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*Monitor CBC with diff
*Absolute Neutrophil Count < 500 or platelet count
< 25,000, stop Ganciclovir
*Administer granulocyte colony-stimulating factor (Neupogen) for the neutropenia

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Other Adverse Effects of Ganciclovir Administration

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*Renal insufficiency
*Fever
*HA
*Phlebitis
*Rash
*Encephalopathy

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Management of Renal Insufficiency due to Ganciclovir

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*Crystallization in renal tubules
*Adequate hydration
*Dose based on ideal body weight
*Adjust dose for renal dysfunction

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Hepatitis C Agents

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*Ribavirin
*Pegylated interferon
*Telaprevir
*Boceprevir

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Sustained Virologic Response

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*patients are cleared of their serum virus
*essentially a cure of the illness

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Negative Outcomes of Hepatitis C

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*carcinoma (heptato-cellular)
*cirrhosis/liver failure

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Ribavirin Formularies

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*Orally
*Via inhalation
*IV or intra-ventricular available through the CDC

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MOA of Ribavirin

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*unknown MOA or how it works on viruses
*not a directly-acting antiviral

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Most Adverse Effect of Ribavirin

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*Anemia

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Triple Therapy Treatment for Hepatitis C

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*Peg-Interferon + Ribavirin + Telaprevir
*Peg-Interferon + Ribavirin + Boceprevir

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MOA of Telaprevir & Boceprevir

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*NS 3/4 A Protease Inhibitors

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Adverse Effects Related to Telaprevir Administration

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*ANEMIA
*rash
*ANAL ITCHING

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Adverse Effects Related to Boceprevir

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*ANEMIA
*metallic taste

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Labs to Monitor during Hepatitis C Treatment

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*CBC & LFTs q 4 weeks*

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Possible Side Effects with Hepatitis C Treatment

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*Profound ANEMIA
*Leukopenia
*Thrombocytopenia
*Neurologic: fatigue, depression, insomnia
*Flu-like Sx: fever, myalgias, HA
*Pulmonary syndrome/infiltrates
*Pancreatitis
*Rash
*Thyroid dysfunction
*GI intolerance

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Management of Anemia with Hepatitis C Therapy

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*pre-treat with iron supplements
*avoid use with AZT (Zidovudine) or marrow toxic drugs
*Epogen 40,000 IU/week
*Dose reduction of interferon/ribavirin, if needed

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Management of Leukopenia with Hepatitis C Therapy

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*Granulocyte-colony-stimulating factor 300 mcg three times/week to maintain absolute neutrophil count >750
*Dose reduce interferon, if needed

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Management of Thrombocytopenia with Hepatitis C Therapy

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*Maintain platelets >50,000
*Dose reduce interferon, if needed

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Management of Neurologic Side Effects with Hepatitis C Therapy

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*Celexa (SSRI) recommended = least # of drug interactions/quick onset of action)
*Discontinue therapy if severe depression or suicidality develops

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Management of Flu-like Sx with Hepatitis C Therapy

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*pre-treat with Tylenol or NSAIDs
*take interferon before bed ("sleep off" side effects)
*stay well-hydrated (8-10 glasses of water daily)

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Safe Amount of Tylenol Administration in Liver Patients

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*limit Tylenol to 2 grams daily

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Management of Pancreatitis with Hepatitis C Therapy

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*Monitor lipase

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Management of Rash with Hepatitis C Therapy

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*Mild rash, can use antihistamines
*Significant drug rash = discontinue therapy

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Management of Thyroid Dysfunction with Hepatitis C Therapy

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*Monitor TSH every 12 weeks*

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Management of GI Intolerance with Hepatitis C Therapy

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*Take Ribavirin with food
*Drink 8-10 glasses of water daily
*Eat small, frequent meals

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Antiviral Effects of Interferons

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*glycoproteins
*interferes with viral growth
*responsible for complex, antiviral, immunomodulating, & anti-proliferative effects

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3 Classes of Interferons

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1) Alpha
2) Beta
3) Gamma
*ONLY INTERFERON ALPHA HAS BEEN APPROVED FOR VIRAL TREATMENT*

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MOA of Interferons

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*induces changes in the infected or exposed cell to promote resistance to the virus
*NOT directly virucidal or virustatic
*Induces several enzymatic activities that promote an antiviral state

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Enzymatic Activities of Interferons that Promote an Antiviral State

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*proteins that inhibit synthesis of viral RNA
*proteins that cleave viral DNA
*proteins that inhibit viral mRNA
*alterations of the cell membrane that inhibit the release of replicated virions

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__________________ currently make-up the backbone of Hepatitis C therapy.

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Interferons

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MOA of Oseltamivir (Tamiflu)

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*PO neuraminidase inhibitor
-cleaves terminal sialic acid residues on glycoconjugates & destroys receptors
-newly formed virions adhere to cell surface & limit spread

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Oseltamivir (Tamiflu) Spectrum of Activity

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*Influenza A & B in both children & adults
*Avian influenza
*H5H1 disease

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Adverse Effects of Oseltamivir (Tamiflu)

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*nausea/vomiting
*HA

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Resistance with Oseltamivir (Tamiflu) Administration

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*H275Y in neuraminidase

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Oseltamivir (Tamiflu) decreases the number of symptomatic days by _________________________.

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*1.3 days

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How soon should Oseltamivir (Tamiflu) therapy be initiated?

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*within 72 hours of sx onset
*unless patient is very sick/in respiratory distress from the flu; Tamiflu will be started regardless of the flu onset

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How many different agents should be used in the treatment of HIV?

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*at least 3 active drugs for HIV treatment
*mono-therapy should NEVER be used for HIV

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Backbone of HIV Therapy/Treatment

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*2 NNRTIs + an agent from another drug class

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6 Different Classes of Anti-retroviral Agents

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1) NRTIs
-NucleoSide reverse transcriptase inhibitors
-NucleoTide reverse transcriptase inhibitors
2) Non-nucleoside-reverse transcriptase inhibitors (NNRTIs)
3) Protease Inhibitors
4) CCR5 Antagonists
5) Integrase Inhibitors
6) Fusion Inhibitors

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Function of Entry Inhibitors

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*block the HIV virus from even getting into the host cell

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Function of Reverse Transcriptase

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*transcribes viral RNA into DNA
*Transcriptase inhibitors block this enzyme:
-nucleoside
-nucleotide
-non-nucleoside

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Function of Integrase

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*once the virus is turned into DNA; Integrase integrates the DNA into the host's DNA
*Integrase inhibitors block this enzyme

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Function of Protease

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*virus can become long protein chains
*protease cleaves these protein chains into functional proteins
*Protease inhibitors block this enzyme

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Black Box Warning associated with Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

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*Mitochondrial Toxicities
-pancreatitis
-lactic acidosis
-hepatic steatosis (abnormal retention of lipids)
-peripheral neuropathy

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Other NRTI Side Effects

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*Fatigue
*HA

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NRTIs require intracellular ________________________ for activation.

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*triphosphorylation

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Drug Classification for Tenofovir, Viread, TDF

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*NucleoTide reverse transcriptase inhibitor

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Dosage for Tenofovir, Viread, TDF

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*300 mg PO daily
*Renal dosage adjustment needed

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Adverse Effects with Tenofovir, Viread, TDF Administration

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*Acute Renal Failure
-Fanconi-like Syndrome (RARE)

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Drug Classification for Zidovudine, Retrovir, AZT

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*NRTI

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Dosage for Zidovudine, Retrovir, AZT

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*300 mg PO BID
*need renal dose adjustment

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Adverse Effects of Zidovudine, Retrovir, AZT Administration

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*Profound ANEMIA
*BONE MARROW SUPPRESSION
*myopathy

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Formularies for Zidovudine, Retrovir, AZT

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*Liquid
*Injection
*Tablet
*IV

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Special Use for IV form of Zidovudine, Retrovir, AZT

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*Used intra-partum for HIV-infected mothers to prevent vertical transmission to the infant

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Drug Classification for Abacavir, Ziagen, ABC

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*NRTI

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Dosage of Abacavir, Ziagen, ABC

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*300 mg PO bid OR
*600 mg PO daily
**NO renal adjustment necessary

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Metabolism of Abacavir, Ziagen, ABC

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*Metabolized by alcohol dehydrogenase & glucuronyl transferase

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Formularies of Abacavir, Ziagen, ABC

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*Liquid
*Tablet

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Fatal Adverse Reaction with Abacavir, Ziagen, ABC Administration

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**Hypersensitivity Reaction**
*Perform genotype test prior to administration, HLA*5701
- + will have hypersensitivity reaction
* - will not have hypersensitivity reaction
**NEVER re-challenge a patient with a hypersensitivity reaction**

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MOA of Protease Inhibitors

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*inhibits protease enzyme, preventing maturation of HIV virions

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Adverse Side Effects of Protease Inhibitors

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*METABOLIC SYNDROME*
-dyslipidemia (elevated LDL, triglycerides)
-insulin resistance (glucose intolerance)
-lipodystrophy
-lipoatrophy
-nausea/vomiting/diarrhea
-cardiovascular side effects

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Lipodystrophy

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*"buffalo hump"
*"Crix" belly
*"protease paunch"-central obesity with anorexic limbs
*increased abdomen & breast size

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Lipoatrophy

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*facial & buttock wasting
*sunken cheeks
*weight loss
**Mostly seen with NRTI use**

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Major Concern with Protease Inhibitors

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*many drug interactions
*potent CYP P450 inhibitor

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MOA of Ritonavir, Norvir, RTV

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*used for its' drug interaction capabilities to improve the effects of other protease inhibitors
*protease inhibitor

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Dosage of Ritonavir, Norvir, RTV

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*100-200 mg PO daily or bid
*take with food

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Adverse Effects with Ritonavir, Norvir, RTV Administration

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*N/V/D
*tactile disturbances
*circumoral parenthesis

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Storage of Ritonavir, Norvir, RTV

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*capsules must be refrigerated
*can be out for 30 days
*tablets do NOT have to be refrigerated

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Adverse Events with Atazanavir, Reyataz, ATV

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*Least metabolic complications
*asymptomatic hyper-bilirubinemia
*prolongation of PRI

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Drug Interactions with Atazanavir, Reyataz, ATV

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*Avoid PPIs, H2 blockers, & antacids
*No acid suppression; needs acidic environment for absorption

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Drug Classification for Atazanavir, Reyataz, ATV

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*Protease Inhibitor

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Drug Classification for Darunavir, Prezista, DRV

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*Newer Protease Inhibitor

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Dosage for Darunavir, Prezista, DRV

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*600 mg PO bid + Ritonavir 100 mg PO bid
*800 mg PO daily + Ritonavir 100 mg daily

*Used for naïve patients
*Experienced patients with no DRV mutations
*Take with food

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Adverse Effects with Darunavir, Prezista, DRV

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*Rash
*Sulfamoiety; avoid in patients with sulfa allergies

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Drug Classification for Lopinavir/r, Kaletra, LPV/r

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*Protease Inhibitor
*Co-formulated with Ritonavir

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Dosage for Lopinavir/r, Kaletra, LPV/r

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*400 mg / 100 mg PO bid
*Protease Inhibitor Naïve:
-800 mg / 200 mg PO daily

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Adverse Effects with Lopinavir/r, Kaletra, LPV/r

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*hyperlipidemia
*n/v/d