Antiviral Therapy Flashcards
Name the five major classes of antiretroviral medications. What are the recommendations for antiretroviral therapy? What is HAART? What are the recommendations? What is the goal of HAART? One reistance develops, is it permanent? What is resistance directl associated with? What do we do with resistance?
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) (a subclass of this group is the Nucleotide RTIs [tenofovir]), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), Protease Inhibitors (PIs), Entry Inhibitors (enfuvirtide, CCR5 antagonists), Integrase Inhibitors. Antiretroviral therapy is recommended for all HIV-infected individuals – the strength of recommendation depends upon pre-treatment CD4 levels – commitment to therapy is PIVOTAL to avoid mutation. HAART is “highly-active anti-retroviral therapy” – probably all therapy nowadays is highly-active; nevertheless, this is COMBINATION THERAPY: Use multiple classes of agents – typically 3 drugs representative of 2 classes (save 1 class in case of mutation & resistance). Usually, 2 NRTIs are used + PI w/ ritonavir boosting or NNRTI or Integrase Inhibitor. Goal of HAART: Suppress viral load – undetectable viral load (
Name the most important NRTIs. Which can be used in combination? What’s the MOA? What are the class side effects? What are the individual side effects? Which is the safest?
lamivudine, abacavir, emtricitabine, tenofovir. Combinations: lamivudine/abacavir & emtricitabine/tenofovir. MOA: viral DNA chain termination via inhibition of RT. Tenofovir: nephrotoxicity; Abacavir: hypersensitivity reaction (IMMEDIATELY stop the drug and DO NOT restart – the reaction will be worse; this is a genetical susceptibility, so HLA testing can avoid this); Lamivudine/emtricitabine: few – the safest!!; Zidovudine: anemia; Class side effects: Lactic acidosis (much less common with new agents), GI side effects.
Name the most important NNRTIs. MOA? Side effects?
efavirenz, nevirapine, rilpivirine, etravirine (“efa nevir riles etra”). MOA: Bind ot - and directly inhibit RT. Efavirenz: CNS – drowsiness, vivid dreams, teratogenic (most teratogenic of all the antivirals we talk about); Nevirapine: rash, hepatitis incl. hepatic necrosis; Etravirine: rash, increased LFTs; Rilpivirine: rash, QT prolongation.
Name the most important PIs. MOA? What is ritonavir boosting? Class toxicities?
darunavir, lopinavir/ritonavir, ritonavir, atazanavir, fosamprenavir. (“darun & lopes rit ata fos”). MOA: Bind within active pocket of protease and inhibit it. Ritonavir at low doses enhances blood levels of other PIs via P4503A4 inhibition (this is an EXTREMELY POTENT inhibitor of P4503A4). Effects: Reduce frequency of dosing/pill burden, improve adherence, reduce adverse drug reactions/effects, improved ability to suppress strains of resistant virus, improve regimen efficacy!! THIS IS almost ALWAYS co-administered with a PI. Class toxicities: GI intolerances, Metabolic toxicities (!! – dyslipidemia, hyperglycemia, lipodystrophy).
What is the HIV fusion inhibitor? MOA? How is this administered and why? Side effects? What is the CCR5 antagonist? Side effects? What is the caveat of using this drug?
enfuvitiride. MOA: Bind to gp41 and prevent viral fusion and entry. This is injected because it is a peptide and would be broken down by the GI. Side effects: Local injection reactions, pneumonia, hypersensitivity rxn. This is considered a “salvage drug.” CCR5 antagonist: Maraviroc. Side effects: This is a relatively safe drug – rare serious hepatotoxicity. This can only be used in those in which HIV is using CCR5 as a co-receptor. Also considered a “salvage drug.”
What are the integrase inhibitors? Adverse effects?
raltegravir, elvitegravir, dolutegravir. Adverse effects: generally considered the safest drugs after lamivudine/emtricitabine.
Is there a vaccine for Hep C? Can we cure this? What is SVR? Do we use combination therapy to treat Hep C like in HIV?
No vaccine. This is considered curable!! SVR = “sustained viral response” – This is considered equivalent to a cure. SVR = undectable HCV RNA 12-24 weeks after therapy. Combination therapy is the standard of care!
What are the “disappearing” drug classes that were once used to treat Hep C? MOAs? Side effects?
Interferon & Ribavirin. Interferon MOA: Induce interferon-stimulated genes (ISGs) that help establish an antiviral state within cells (not virus-specific); usually used in pegylated form and given SQ 1X/week. Numerous toxicity concerns!! – Flu-like symptoms, cytopenias, depression, fatigue – Difficult to finish treatment course
Many patients with contraindications: Unstable psychiatric problems, baseline severe cytopenias, etc. Ribavirin: nucleoside analog. Major side effect: hemolytic anemia, teratogenic. These drugs suck to have to take!! Patients hated them!!
What are the “game changer” drugs in the treatment of Hep C? Give MOA, side effects.
Nucleoside/Nucleotide NS5B Polymerase Inhibitors (sofosbuvir); NS5A Inhibitors (ledipasvir); NS3/4A Protease Inhibitors (simeprevir, telaprevir, boceprevir). Sofosbuvir: MOA: Inhibitor of HCV NS5B RNA-dependent RNA polymerase; once phosphorylated, competes with natural viral nucleotide (uridine) to cause chain termination of HCV RNA – Active across all HCV genotypes. Toxicity concerns: Appears relatively safe. Fatigue, headache, GI side effects, anemia possible. Ledipasvir: Available as
part of combination product (sofosbuvir/ledipasvir). MOA: Inhibits HCV NS5A, a viral phosphoprotein required for viral replication. Toxicity concerns: Appears relatively safe. Fatigue, headache, GI side effects possible. Simeprevir, Telaprevir, Boceprevir: MOA: Prevent viral maturation through the inhibition of protein synthesis. Toxicity concerns: differ slightly depending upon the agent anemia, rash, itching, GI side effects, drug interactions.
State the drugs (& their respective prodrugs) used to treat different herpes infections. Why are prodrugs used? MOA of acyclovir and penciclovir? How does the mxn of activation relate to resistance? Acyclovir adverse effects? How should ganciclovir be given? What are adverse effects? What is Foscarnet? Adverse effects?
Acyclovir (Valacyclovir): HSV, VZV. Penciclovir (Famciclovir): HSV, VZV. Ganciclovir (Valganciclovir): CMV (also effective for HSV, VZV). Prodrugs are used because of low availability of these drugs. Acyclovir, Penciclovir MOA: After phosphorylation by viral thymidine kinase, acyclovir triphosphate competes with DNA analogues to cause viral DNA chain termination. Mutations in thymidine kinase can result in resistance! Acyclovir: Toxicity concerns – Central nervous system malaise, headache, confusion, nausea, vomiting, diarrhea, renal dysfunction seen with higher doses of IV therapy due to drug crystallization in the kidney (dose-related!). Ganciclovir should be given IV because of poor availabilty PO. Adverse effects: Myelosuppression!! (neutropenia 25-40% of patients), Monitor CBC – may need to d/c drug, CNS toxicity (HA, seizures, confusion), Hepatotoxicity, GI intolerance in limited patients. Foscarnet: Inhibitory effect on herpesviruses and HIV
MOA: directly inhibits herpesvirus DNA polymerase or HIV reverse transcriptase; Does not undergo significant intracellular metabolism – Generally active against acyclovir / penciclovir /ganciclovir resistant viruses!! Adverse effects: Nephrotoxicity (occurs in 1/3 of patients) – Dose limiting side effects!! Electrolyte/Metabolic abnormalities: (10-45% of patients)Hypo / hypercalcemia, Hypo / hyperphosphatemia, Hypomagnesemia, Hypokalemia – Infuse at maximum rate of 1 mg/kg/minute to minimize these effects, CNS side effects (1/4 of patients), tremor, irritability, seizures (up to 10%), hallucinosis, myelosuppression.
What remains the best strategy to treat influenza? What is the class of drugs used to treat the flu? Name the 2 that are used. Do these drugs work? Side effects? Does chemoprophylaxis work?
VACCINATE!! Neuraminidase inhibitors (Neuraminidase is enzyme critical in penetration of respiratory tract mucus and in the release of virus from infected cells): Oseltamavir, Zanamavir. The drugs work if given w/in 48 hours of the onset of symptom onset and if continued for 5 days – they reduce the risk of complication and shorten the illness by 30% time (usually 1 day). They may be especially helpful in the critically ill. Side effects: GI side effects including nausea/vomiting/diarrhea, neuropsychiatric events reported, agitation, anxiety, altered mental status, (w/ zanamavir) inhaled therapy bronchospasms possible. Chemoprophylaxis provides efficacy – particularly among individuals who have not been vaccinated.
