Antiviral therapy

1. Antiviral therapy

2. Practical Points • No treatment for most viral disease • Prevention is the mainstay • Vaccinations • Social distancing • Hand hygiene • Antibiotic stewardship

3. Overview • Identify the few situations where viral infections are treatable • Understand BASIC mechanism of action (when known) of appropriate antiviral, window when intervention is meaningful, resistance patterns and toxicity of treatment N.B. Viral hepatitis will be discussed later this week and will not be covered

4. Case 1 • 35 year old male with 4 days of rhinorrhea, nasal congestion and pharyngitis; he mentions this incidentally during his routine follow up for HLP. • 4 children at home, 2 of them are under 5 and in day care

5. Case 1 • What is the likely pathogen? • What is the only intervention shown to have efficacy in this situation? (despite numerous trials) • When is the therapeutic window? • When do we start worrying this might not be a virus and feel inclined to treat (i.e. acute bacterial sinusitis)?

6. Rhinovirus • What is the only intervention shown to have efficacy in this situation? (despite numerous trials) • Zinc (nasal gel better than lozenge) • Inhibits RNA polymerase • – not echinacea, Vit C • When is the therapeutic window? • First 24 hrs, and only decreases time to resolution by 1-2 days

7. Case 2 • You are on your geriatric rotation in February and while on rounds the charge nurse informs you of 6 residents with myalgias, respiratory illness and fever, 2 of whom were hospitalized yesterday • The remaining 4 have become symptomatic over the last day

8. Case 2 • What is the viral likely pathogen? • What is the significance of the month and setting of infection? • What is your intervention? • What info would be helpful in making your decision? • What aspects of drug toxicity and tx spectrum are important to consider? • What could have prevented this outbreak? (possibly) – think broadly (i.e. introduction and propagation)

9. Influenza • What is the significance of the month and setting of infection? • Waning immunity in nursing home residents from initial vaccination (and overall poor response) • What is your intervention? • Neuraminidase inhib +/- rimantidine* • (w/i 48 hrs sx) • What info would be helpful in making your decision? • Current influenza activity in the community • http://www.cdc.gov/flu/weekly *http://www2a.cdc.gov/HAN/ArchiveSys/ViewMsgV.asp?AlertNum=00279

10. Influenza • What aspects of drug toxicity and tx spectrum are important to consider? • Oseltamavir – NA/particle cleavage and release; GI sx • Zanamavir – NA/particle cleavage and release; asthma exacerbation, requires cooperative patient • Rimantidine – ? Viral Uncoating; (only good for flu A) • Ribavirin – guanosine analogue; not FDA approved for flu, off-label for combo with oselt

11. Influenza • What could have prevented this outbreak? (possibly) – think broadly (i.e. introduction and propagation) • Revaccination of residents (?) – probably not • Compliance with vaccination of HCPs (usu <50%) - YES 50K die and 350K are hospitalized each year from SEASONAL influenza in the US

12. Avian Influenza – 1997 and forward • Total # of human deaths = 254 (63% case fatality) • # countries = 15, leading: Indonesia, Viet Nam • Animal control (vaccination and culling) controls the infection • Government compensation is key • Use of PPE, avoidance of bird markets, thorough cooking of potentially infected meat • Neuraminidase inhibitors work, theoretically • Increasing resistance • Human vaccine in the works http://www.who.int/csr/disease/avian_influenza/country/cases_table_2009_02_09/en/index.html

13. Case 3 • 22 yo active duty male presents to sick call with this eruption

14. Case 3 • What two viruses is he infected with? (at a minimum) • Describe the treatment options for both • What additional information would be helpful in making a decision • Clinical • laboratory

15. HIV Antiretroviral treatment is: • Complex (and evolving)* • Requires extreme dedication • Selection guided by genotype/phenotype • Ideally at least 3 active agents • Response should be monitored • Toxicity monitored and offset (?more meds) • No vaccine in the foreseeable future *http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7

16. HIV • Monitor toxicity • Allergy / hypersensitivity • Genetic screening for abacavir • Long term effects • Protease inhibitors (PIs) – lipids, glucose • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) – lipids (TG), hepatic • nucleoside reverse transcriptase inhibitors (NRTIs) – renal, marrow, neuropathy • Integrase inhibitors – myositis • CCR5 receptor blocker - hepatitis

17. Herpesviridae • Acyclovir and its derivatives • fam, val • Increased bioavailability (and cost), same spectrum • Inhibits viral DNA polymerase • Thymidine kinase mutants  resistance • HSV>VZV>>EBV≠CMV (intrinsically resistant) • Iv form --? Crystalluria/stones

18. Herpesviridae • Foscarnet or ganciclovir: • CMV and acyclovir resistant HSV • Toxicity: • foscarnet: renal tox, sz, • gancyclovir: marrow suppression

19. Case 4 • 30 yo unmarried active duty male presents with the following lesions which have developed over several months • He reports unprotected sex with 3 partners over the last year

20. Case 4 • What virus is responsible for these lesions? • What cancers has it been associated with? • What methods of treatment exist? • Major side effects from each? • What further work up should ensue? • What surgical intervention would decrease STD transmission to his female partners and decrease his risk of cancer?

21. HPV • What cancers has it been associated with? • Cervical • Penile • Anal • What methods of treatment exist? • Physical destruction / removal • Cryo, laser, surgery (pain, scarring) • Local Immune enhancement • Imiquimod (irritation)

22. HPV • What further work up should ensue? • Full STD evaluation – HIV, RPR, gc/chlam, Hep B, Hep C • What surgical intervention would decrease STD transmission and cancer risk to the patient and partners? • circumcision http://www.who.int/hiv/topics/malecircumcision/en/index.html http://www.cdc.gov/hiv/resources/factsheets/circumcision.htm

23. Case 5 • 28 yo female presents to her primary care doctor after developing a painful and itchy blisters on her face 1 week after seeing her boyfriend who has since deployed to Iraq

24. Case 5 • What pre-deployment vaccination is the source for this infection? • What drugs/biologics are available for intervention? • What are indications for treatment? • What are the potential side effects?

25. Poxviridae • Orthopoxviruses (Monkeypox, vaccinia) – potentially life threatening • VIG-IV (allergic reaxn-rigors, fever) • Cidofovir: targets DNA polymerase • nephrotoxic – needs to be given with hydration and probenecid • ST-246: targets viral maturation • ORAL • placebo-like • Works against CDF-resistant strains http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5204a1.htm

26. Poxviridae • Parapoxviruses and molluscum contagiosum – localized, only serious in immunocompromised • Imiquimod, intralesional cidofovir Orf virus infection

27. Case 6 • 8 year old Filipina girl BIB parents 2 weeks after sustaining a bite to the face from a local dog. She is currently exhibiting tremors, slurred speech and she is refusing to eat/drink

28. Case 6 • What virus is responsible for her condition? • What interventions are recommended in the acute setting of such a dog bite (asymptomatic patients)? • What recent protocol has saved the lives of at least 2 symptomatic patients? • What is the risk to close contacts/health care providers of this girl?

29. Rabies • What interventions are recommended in the acute setting of such a dog bite (asymptomatic patients)? • RIG (not needed if pre-exposure vax given) • Rabies vaccine • What recent protocol has saved the lives of at least 2 symptomatic patients?

30. Rabies • Milwaukee protocol • Ketamine, midazolam, ribavirin, amantadine • No vaccine/biologic (fear of potentiating immune response) • Potential risk to HCPs • Never been documented • At least 2 non-lab confirmed human-to-human via saliva Rabies in a dog imported from Iraq--New Jersey, June 2008. Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2008 Oct 3;57(39):1076-8. No abstract available.

31. Case 7 • 30 yo female missionary returns from Nigeria with facial/neck edema, fever, conjunctivitis and one bout of bloody emesis. She reports living in a rural village for 1 month and did indulge in the local delicacy of grilled rodent which she helped her host family to prepare.

32. Case 7 • What is the likely viral etiology? • What is the reservoir? • Are healthcare workers at risk for infection? • What drug may be of benefit?

33. Lassa Fever • What is the reservoir? • mastomys • Are healthcare workers at risk for infection? • Yes, contact precautions • What drug may be of benefit? • Ribavirin • Hemolytic anemia, teratogen • Activity against arenaviridae (LF) and bunyaviridae (CCHF)

34. References • Survival after treatment of rabies with induction of coma. Willoughby RE et al. N Engl J Med. 2005 Jun 16;352(24):2508-14. • Combinatorial ribavirin and interferon alfacon-1 therapy of acute arenaviral disease in hamsters. Gowen BB et al. Antivir Chem Chemother. 2006;17(4):175-83. http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/lassaf.htm

35. References cont. • Efficacy of zinc against common cold viruses: an overview. J Am Pharm Assoc (2003). 2004 Sep-Oct;44(5):594-603 • Clinical practice. Prevention and treatment of seasonal influenza. N Engl J Med. 2008 Dec 11;359(24):2579-85 • Successful Treatment in the Monkeypox and Variola Primate Models of Smallpox by the Oral Drug ST-246Antiviral ResearchVolume 74, Issue 3, June 2007, Page A35

36. References cont. • http://www.cdc.gov/mmwr/preview/mmwrhtml/rr57e507a1.htm (human rabies prevention, 2008 recommendations)