Ch 34 Antiviral Drugs

Influenza A

Influenza B

Respiratory synctial virus (RBV)

Viral respiratory tract infections

Immunization

Preferred approach against influenza

Oseltamivir

Zanamivir

Neuraminidase inhibitor

Influenza A

Influenza B

Neuraminidase inhibitor antiviral spectrum

Inhibits neuraminidase inserted into the host cell membrane to release newly formed virions

Neuraminidase inhibitor mechanism of action

Oseltamivir

Orally active neuraminidase inhibitor prodrug rapidly hydrolyzed by the liver

Inhalation

Zanamivir route of administration

Gastrointenstinal discomfort

Nausea

Common AE of oseltamivir

Respiratory tract irritation

Common AE of zanamivir

Amantadine

Rimantadine

Adamantane derivatives used for influenza A infections

Not widely used due to widespread resistance

Ribavirin

Used in the treatment of immunosuppressed infants and young children with severe RSV infection

Effective in chronic HPC infections in combination with DAA

Phosphorylates to 5’-phosphate derivative and inhibits guanosine triphosphate formation

Ribavirin mechanism of action

Aerosol

Ribavirin preparation used in treatment of RSV infection

Dose dependent transient anemia

Elevated bilirubin

Common AE of ribavirin

Pregnancy

Contraindication of ribavirin

Peginterferon-a-2a

Subcutaneous solution used to treat chronic HBV

Interferons

Inducible glycoproteins that interfere with ability of viruses to infect cells

Pegylated

Formulation of interferons that increases size of molecule

Bis-monomethoxy polyethylene glycol

Inhibit viral RNA translation leading to degradation

Interferon mechanism of action

Flu-like symptoms

Fatigue

Mental depression

Bone marrow suppression

Weight loss

Neurotoxicity

Thyroiditis

Common AE of interferons

Inhibits HBV and HIV reverse transcriptases

Phosphorylated to active form to inhibit HBV RNA-depedent DNA polymerase

Lamivudine mechanism of action

Phosphorylated by kinase to diphosphate form leading to termination of chain elongation

Adefovir mechanism of action

Severe exacerbation of hepatitis

Common withdrawal AE of adefovir

Phosphorylate to triphosphate and competes with the natural substrate, deoxyguanosine triphosphate, for viral RT

Entecavir mechanism of action

Entecavir

Effective against lamivudine-resistant strain of HBV

Dosed once daily

Acyclovir

Prototypic antiherpetic therapeutic agent

HSV Type 1 and 2

Varicella-zoster virus (VZV)

Epstein-Barr virus-mediated infections

Acyclovir antiviral spectrum

Acyclovir

Most commonly used in treatment of genital herpes infections

Prophylaxis before bone marrow transplant and post-heart transplant

Phosphorylates to triphosphate and competes with deoxyguanosine triphosphate as substrate for viral DNA polymerase causing premature DNA chain termination

Acyclovir mechanism of action

Valacyclovir

Valyl ester of acyclovir

Greater oral bioavailability

Transient renal dysfunction

Common AE of acyclovir in high dose or dehydrated patient

Cidofovir

Used in treatment of cytomegalovirus (CMV) retinitis in patients with AIDS

Inhibit viral DNA synthesis

Cidofovir mechanism of action

Patients with renal impairment

Patients taking nephrotoxic drugs

Contraindication of cidofovir

Oral probenecid

IV NSS

Coadministered with cidofovir to reduce risk of nephrotoxicity

Foscarnet

Used in CMV retinitis in immunocompromised patients and acylovir-resistant HSV infections

Reversibly inhibits viral DNA and RNA polymerase

Foscarnet mechanism of action

Intravenous

Forscarnet route of administration

Hypocalcemia

Hypomagnesemia

Hypokalemia

Hypo/Hyperphosphatemia

Occurs when taking foscarnet due to chelation with divalent ions

Nephrotoxicity

Common AE of foscarnet

Ganciclovir

Analog of acyclovir with greater activity against CMV

Used in treatment of CMV retinitis in immunocompromised patients and CMV prophylaxis in transplant plants

Valganciclovir

Valyl ester of ganciclovir

Greater oral bioavailability

Severe dose-dependent neutropenia

Common AE of ganciclovir

Carcinogenic

Teratogenic

Boxed warning of ganciclovir

Penciclovir

Administered topically against HSV-1, HSV-2 and VZV

Used in tratment of acute herpes zoster, genital HSV infection and recurrent herpes labialis

Inhibits HSV DNA polymerase

Penciclovir mechanism of action

Famciclovir

Acyclic analog of 2’-deoxyguanosine

Prodrug metabolised to penciclovir

Inhibit incorporation of thymidine triphosphate into viral DNA leading to synthesis of defective DNA

Trifluridine mechanism of action

Trifluridine

Active against HSV-1, HSV-2 and vaccinia virus

Used in treatment of HSV keratoconjunctivitis and recurrent epithelial keratitis

Ophthalmic

Trifluridine preparation available as it is too toxic for systemic use

Transient irritation of the eye

Palpebral (eyelid) edema

Common AE of trifluridine

Antiretroviral therapy

ART meaning; multidrug regimen to suppress replication of HIV and restore CD4 cells

Nucleoside and nucleotide reverse transcriptase inhibitor

NRTI meaning

Nonnucleoside reverse transcriptase inhibitor

NNRTI meaning

Combination of two NRTI with integrase inhibitor

NNRTI

Boosted PI

Initial therapy for HIV

NRTI

First agents available to treat HIV infection

Zidovudine

Lamivudine

Tenofovir

Abacavir

Emtricitabine

Most commonly used NRTI

Tenofovir disoproxil fumarate

Combined with emtricitabine, used for preexposure prophylaxis for individuals with high risk of HIV acquisition

Inhibits HIV reverse transcriptase, DNA chain elongation is terminated due to lack of 3’-hydroxyl group

NRTI mechanism of action

Tenofovir disoproxil fumarate

TDF meaning

Tenofovir aladenamide

TAF meaning

Fewer adverse effects compared to TDF

Abacavir

Metabolized by alcohol dehydrogenase and glucuronyl transferase

Peripheral neuropathy

Pancretitis

Lipoatrophy

Common AE of didanosine and stavudine

Fatal liver toxicity characterized by lactic acidosis

Hepatomegaly with steatosis

Common AE of NRTi

HLA-B*5701

Genetic test to screen patients with abacavir allergy

Binds to HIV RT at an hydrophobic site inducing a conformational change that results in enzyme inhibition

NNRTI mechanism of action

Nevirapine

Delavirdine

Efavirenz

Etravirine

Rilpivirine

NNRTI drugsE

Efavirenz

Rilpivirine

NNRTI recommended in initial antiretroviral regimen

Efavirenz

Safe to use in patients coinfected with TB

Rilpivirine

Smallest tablet size NNRTI

Eltavirine

Second generation NNRTI active against HIV strains

Atazanavir

Darunavir

Protease inhibitor recommended by HIV guidelines

Reversibly inhibits HIV aspartyl protease (retropepsin) that prevents maturation of viral particle

Protease inhibitor mechanism of action

Nelfinavir

Saquinavir

Increased bioavailability with high-fat meals

Indinavir

Decreased bioavailability with high-fat meals

Disturbance in glucose and lipid metabolism

Diabetes

Hypertriglyceridemia

Hypercholesterolemia

Common AE of protease inhibitor

Fat redistribution

Buffalo hump

Common AE in chronic administration of protease inhibitor

Rhabdomyolysis

Drug interaction of PI with simvastatin or lovastatin

Excessive sedation

Drug interaction of PI with midazolam or triazolam

Respiratory depression

Drug interaction of PI with fentanyl

Atazanavir

PI that requires acidic environment for absorption

Combined with ritonavir or cobicistat

Competitively inhibits glucuronyl transferase

Atazanavir mechanism of action

Benign hyperbilirubinemia

Jaundice

PR prolongation

Common AE of atazanavir

Atazanavir

Decreased risk of hyperlipidemia compared to other PI

Darunavir

Initial therapy in treatment-naive HIV-infected patients

Treatment experienced patients with HIV resistant to other PI

Binds to gp41, preventing conformation change

Enfuvirtide mechanism of action

Enfuvirtide

Used for treatment-experienced patients with evidence of viral replication despite ongoing ART

Injection site pain, erythema, nodules

Common AE of enfuvirtide

Enfuvirtide

Must be reconstituted prior administration

Blocks CCR5 coreceptor that works with gp41

Maraviroc mechanism of action

Viral tropism

Test required prior use of maraviroc

Severe hepatotoxicity

Common AE of maraviroc

Raltegravir

Elvitegravir

Dolutegravir

Bictegravir

Integrase strand transfer inhibitor (INSTI)

Integrase inhibitorsI

Inhibits insertion of proviral DNA into the host cell genome

Integrase inhibitor mechanism of action

3 hours

Half life of elvitegravir alone

9 hours

Half life of elvitegravir and cobicistat

Chelation with antacids

Integrase inhibitors should be separated from antacids and polyvalent cations by several hours due to this reason

Ritonavir

Booster that increases bioavailabilty of PI, often allowing longer dosing intervals

Cobicistat

Booster that enhances bioavailability of atazanavir and darunavir and integrase inhibitor elvitegravir

Increased serum creatinine

Inhibits tubular creatinine secretion

Common AE of cobicistat