Overview of Antivirals for HIV, HCV, & VZV Mechanisms of Action and Most Important Side Effects

1. Group A-7Forrest EstesNicholas ClapperNourhene FarhatCourtney DrewSheena FavorsArthur Iskhahov Overview of Antivirals for HIV, HCV, & VZV Mechanisms of Action and Most Important Side Effects

2. Amantadine MOA The M2 protein: • A viral envelope protein. • Facilitates viral uncoating upon entry into the cell. • Amantadine blocks the function of this protein, and thus viral infectivity. “A Man 2 Dine” takes off his coat: • A refers to Influenza A and the fact that it can cause problems with the cerebellA. • 2 refers to the M2 protein. • Coat refers to uncoating. Clinical Use • Influenza A treatment & prevention. • While the mechanism has not been fully described, it is also known to increase dopamine levels and thus is utilized in the treatment of Parkinson’s. Toxicity • Ataxia, dizziness, slurred speech. • Note that Ramantidine is an alternative that doesn’t cross the BBB  fewer CNS side effects. • Also note that a mutated M2 = resistance, which is the case in 90% of Influenza A virus.

3. Zanamivir, Oseltamivir MOA Neuraminidase: • One of two viral envelope glycoproteins (the other being hemagluttinin). • After assembly within the infected cell the virus approaches and disrupts the membrane in order to release itself from the host cell. • Neuraminidase is the viral tool that mediates the membrane disruption. • Block neuraminidase  no viral release. Clinical Use • Influenza A & B treatment. Toxicity • NVD, Headache, stomach pain. Sources First Aid for the USMLE Step 1 Nature Reviews – http://www.nature.com/nrd/journal/v6/n12/fig_tab/nrd2400_F2.html CDC website – http://www.cdc.gov/flu/protect/hiv-flu.htm

5. Acyclovir • MOA: Guanosine analog, phosphorylated by thymidine kinase of HSV/VZV to inhibit viral DNA polymerase via chain termination. • Resistance occurs in case of altered or absent thymidine kinase • Uses: prototypic anti-herpetic agentHSV, VZV, EBV. • DOC for HSV encephalitis • HSV prophylaxis prior to bone marrow or major organ transplants. • Adverse effects: depend on route of administration • Topical: local irritation • Oral: HA/N/V/D • IV: transient renal dysfunction if dehydrated or high doses • FIRST AID: “generally well tolerated”

6. Gancyclovir • MOA:Guanosine analog, phosphorylated by viral enzymes, CMV viral kinase or HSV/VZV thymidine kinase to inhibit viral DNA polymerase. • Resistance occurs via mutated viral enzymes • Uses: CMVmore potent drug than acyclovir • CMV retinitis • CMV prophylaxis in transplant patients • Adverse effects: dose-dependent neutropenia, leukopenia, thrombocytopenia, renal toxicity. • More powerful, thus more toxic to host enzymes than acyclovir

7. Sources • FIRST AID USMLE 2011. • Lippincott’s Pharmacology, 4th edition.

9. Outline • Foscarnet • Mechanism of action • Clinical Use • Toxicity and Mechanism of Resistance • Cidofovir • Mechanism of Action • Clinical Use • Toxicity

10. Foscarnet

11. Mechanism of Action(Foscarnet) • Viral DNA polymerase inhibitor that binds to the pyrophosphate- binding site of the enzyme FOScarnet= pyroFOSphate analog

12. Clinical Use(Foscarnet) • CMV retinitis in immunocompromised patients • When ganciclovir fails

13. Toxicity and Mechanism of Resistance(Foscarnet) • Nephrotoxicity • Mechanism of resistance is due to mutated DNA polymerase

14. Cidofovir

15. Mechanism of Action(Cidofovir) • Selectively inhibits viral DNA polymerase

16. Clinical Use(Cidofovir) • CMV retinitis treatment in AIDS pts.

17. Toxicity(Cidofovir) • Nausea, vomiting, Headache • Nephrotoxicity, hepatotoxicity • Black box Warning: • Renal impairment • Neutropenia • Teratogen

19. Protease Inhibitors- end in navir • HIV-1 protease cleaves the polypeptide products of HIV mRNA to make functional proteins • Protease Inhibitors prevent this step  no maturation of new virions • NAVIR TEASE a proTEASE

20. Protease Inhibitor Side Effects • Hyperglycemia • GI intolerance (nausea, diarrhea) • Lipodystrophy- • Redistribution of fat from extremities to midsection • Thought to occur from inhibition of hepatic chylomicron uptake and triglyceride clearance

21. Protease Inhibitor Side Effects • Ritonavir is a cytochrome P-450 inhibitor • Inhibitors= MAGIC RACKS • Macrolides • Amiodarone • Grapefruit Juice • Isoniazid • Cimetidine • Ritonavir • Acute Alcohol Abuse • Ciprofloxacin • Ketoconazole • Sulfonamides

22. Integrase Inhibitors • Raltegravir • HIV integrase allows the HIV virus to be integrated into the host DNA, which is necessary for replication • Side effects- hypercholesterolemia

23. Zidovudine Didanosine Zalcitabine Stavudine Lamivudine Abacavir • MOA: Competitively inhibits nucleotide binding to reverse transcriptase • Activated by thymidine kinase through phosphorylation NRTIs • Prophylaxis= Ziduvudine • fdas = Ziduvudine NRTI, Y U Need Thymidine Kinase?!?! • Toxic Side Effects: • Bone Marrow Suppression • Peripheral Neuropathy • Lactic Acidosis • Pancreatitis • Hepatic Steatosis • Megaloblastic anemia (ZDV) • Hypersensitivity (ABA)

24. NNRTIs • Nevirapine • Efavirenz • Declaviridine • MOA: NONcompetitively inhibits reverse transcriptase • Does not get activated by thymidine kinase through phosphorylation • Toxic Side Effects: • Same as NRTIs • Rash • Efivarenz can test false (+) for cannabanoids Efivarenz Yea, sure…

25. Reference • First aid

26. Ribavirin • Mechanism of Action • Inhibits synthesis of guanine nucleotides by inhibiting IMP dehydrogenase • Clinical Use • RSV, chronic hepatitis C • Toxicity • Hemolytic anemia

27. Interferons • Mechanism of Action • Glycoproteins that are synthesized by virus infected cells that block viral replication. • Clinical use • IFN-αchronic hepatitis B&C, Kaposi sarcoma • IFN-βMS • IFN-γNADPH oxidase deficiency • Toxicity • Neutropenia

28. Citations • First Aid USMLE Step1 • USMLE Rx Qbank

29. Question 1 You have recently diagnosed one of your young patients with HIV. While this patient is very upset with her diagnosis, she is determined to do whatever is needed to maintain her current healthy state. To that end, flu season is approaching and she would like to know if there is anything that can be done to help her avoid the flu. Which of the following is not indicated in HIV positive patients for the treatment and prevention of the flu? • Amantadine • Nasal Spray Vaccine • Oseltamavir • Inactivated Flu Vaccine • Ramantadine

30. Question 1 – Answer and Explanation You have recently diagnosed one of your young patients with HIV. While this patient is very upset with her diagnosis, she is determined to do whatever is needed to maintain her current healthy state. To that end, flu season is approaching and she would like to know if there is anything that can be done to help her avoid the flu. Which of the following is not indicated in HIV positive patients for the treatment and prevention of the flu? • Amantadine • Nasal Spray Vaccine • Oseltamavir • Inactivated Flu Vaccine • Ramantadine The flu is a serious illness, and HIV positive individuals are at a higher risk of contracting the flu as well as suffering from it’s potential sequelae. Therefore it is recommended that HIV positive individuals take the necessary precautions to avoid becoming sick with the flu. As per vaccinations, HIV positive individuals have the same contraindications to the inactivated flu vaccine as the general population (chicken egg allergies, etc.); however, live attentuated vaccines (Choice B) are completely contraindicated in conditions such as immune suppression, asthma, and pregnancy. Amantadine, oseltamavir, and ramantadine (Choices A, D, and E) are all medications used in the treatment and prevention of the flu that carry no contraindications in HIV positive patients.

31. Question 2 • Acyclovir and gancyclovir are similar drugs with subtle differences that influence their efficacy against viruses. Which of these answers is true about the similiarities and differences between the two drugs? • Gancyclovir utilizes viral enzymes for activation while acyclovir is administrated in active form. • Acyclovir is activated by host nuclear enzymes and gancyclovir is not. • Gancyclovir is efficacious for all forms of Herpes viruses while acyclovir is only effective against HSV-1,2. • Both drugs are well tolerated and have no significant side effects. • Resistance to the drugs occurs via similar mechanisms.

32. Question 2 – Answer and Explanation • Both drugs need viral enzymes for phosphorylation. • Both drugs need viral enzymes for phosphorylation. • Gancyclovir is effective against CMV, while acyclovir is the prototypical anti-herpetic drug, useful against HSV, VZV, and EBV. • While acyclovir is well tolerated, gancyclovir has a dangerous dose-dependent neutropenia, leukopenia, and thrombocytopenia in addition to renal toxicity. • Resistance to both drugs occur via mutation or complete absence of viral DNA kinases. In either case, a deficient activity of the viral enzymes causes inactivation of the anti-viral drugs.

33. Question 3 • A 48 year old female presents to your office complaining of change in her body habitus. She says her legs “are like sticks,” while her “belly is getting bigger.” Exam shows loss of adipose tissue from her extremities and gluteal region with increase of abdominal girth. Which HIV drug could have caused this? • A. Nevirapine • B. Zidovudine • C. Lopinavir • D. Raltegravir • E. Tenofovir

34. Question 3 – Answer and Explanation • A- Nevirapineis an NNRTI. These drugs are not known for causing lipodystrophy. • B- Zidovudine is an NRTI- These are not known or causing lipodystrophy. • C- Lopinavir is the only drug listed that is a protease inhibitor, known for causing lipodystrophy. Glucocorticoids can also cause fat redistribution by causing a Cushing’s syndrome. • D- Raltegravir is an integrase inhibitor. These are not know for causing lipodystrophy. • E- Tenofavir is an NRTI. These are not known for causing lipodystrophy.

35. Question 4 • A former prostitute learns she has become pregnant. During her prenatal visits, she tests positive for HIV. Also tests positive for cannabanoids. Which drug should she be started on for prophylaxis? • Zidovudine • Nevirapine • Efavirenz • Zalcitabine • Abacavir

36. Question 5 • A 9-year-old girl is admitted to the hospital with a bout of severe pneumonia. She has a history of recurrent pneumonia, skin abscesses, and two bouts of bacteremia that have led to sepsis. A lung biopsy reveals numerous lesions as shown in the image below. Acid-fast staining of the tissue section is unrevealing, and cultures from a bronchial lavage demonstrate heavy growth of Staphylococcus aureus. A nitroblue tetrazolium dye reduction test is negative. What antimicrobial would be most appropriate for her disease?ββ • A. IFN-γ • B. IFN-β • C. IFN-α • D. Foscarnet • E. Ribavirin

37. Question 5 – Answer and Explantion • A 9-year-old girl is admitted to the hospital with a bout of severe pneumonia. She has a history of recurrent pneumonia, skin abscesses, and two bouts of bacteremia that have led to sepsis. A lung biopsy reveals numerous lesions as shown in the image below. Acid-fast staining of the tissue section is unrevealing, and cultures from a bronchial lavage demonstrate heavy growth of Staphylococcus aureus. A nitroblue tetrazolium dye reduction test is negative. What antimicrobial would be most appropriate for her disease?ββ • A. This girl has Chronic Granulomatous Disease (CGD), caused by a defect in the oxidative burst system used by phagocytes in the intracellular killing of pathogens. The negative nitroblue tetrazolium dye reduction test is diagnostic of CGD, indicating that oxidative burst failed to occur. Therefore, the proper treatment would be IFN-γ. • B. IFN-β use in MS • C. IFN-αused to treat chronic Hep b and C, Kaposi sarcoma • D. Foscarnet used to treat CMV retinitis in immunocompromised patients when ganciclovir fails; acyclovir-resistant HSV • E. Ribavirin used to treat RSV, chronic hepatitis C