Acyclovir for the Prevention of Herpes Simplex Mucositis During Chemotherapy

1. Acyclovir for the Prevention of Herpes Simplex Mucositis During Chemotherapy Sukhjinder Sidhu Interior Health Pharmacy Resident Critical Care Rotation June 12, 2014

2. Learning Objectives • By the end of this 30-min session the audience should be able to: • Describe the pathophysiology of chemotherapy induced mucositis • Be able to explain the management of mucositis • Be able to explain the evidence for acyclovir prophylaxis of herpes simplex in patients being treated with chemotherapy

3. Our Patient

4. Review of Systems - PRH

5. Course in Hospital - PRH

6. Review of Systems - KGH

7. Microbiology

8. Course in Hospital - KGH

9. Current Problems & MedicationsJune 3

10. DTPs • JM is actively bleeding and receiving inappropriate DVT prophylaxis with heparin • JM is receiving too high a dose of pantoprazole for his lower GI bleed and is at risk of unnecessary adverse effects • JM is at risk of uncontrolled pain secondary to a low dose of hydromorphone for his oral mucositis • JM is at risk of HSV oral mucositis recurrence secondary to not receiving acyclovir prophylaxis prior to his next round of chemotherapy • JM requires dosage adjustments of his cisplatin and etoposidechemotherapy secondary to decreased renal function • JM may require filgrastim prophylaxis secondary to neutropenia experienced during first cycle of chemotherapy

11. Infection with HSV1 • Patients seropositive for HSV antibodies have a 70-80% risk of reactivation • Immunosuppression can activate the latent virus and lead to severe oral infections • Results in rash of skin and mucous membranes • Recurrent HSV1 infection in immunocompromised patients may be more aggressive, painful and slower to heal

12. Oral Mucositis • Inflammatory and/or ulcerative lesions of the oral and/or GI tract • Common side effect of cytotoxic chemotherapy • Damages proliferating cells at the base of the mucosal squamous epithelia • Consequences • Pain • Difficulty swallowing food • Infection risk

13. Oral Mucositis • WHO Grading Score • Grade 0: no objective findings, function irrelevant • Grade 1: erythema + pain, function irrelevant • Grade 2: ulceration, ability to eat solids • Grade 3: ulceration, ability to eat liquids • Grade 4: ulceration, nothing by mouth • Extent or size of ulcers is not a driver

14. Goals of Therapy • Prevent reactivation of herpes simplex virus and mucositis during chemotherapy • Manage pain secondary to mucositis • Improve quality of life • Prevent adverse events associated with drug therapy

15. Therapeutic Approach • Watchful waiting and initiate antivirals if mucositis worsens • Oral valacyclovir • Oral acyclovir • Parenteral acyclovir

16. Acyclovir • Acyclovir triphosphate acts as a competitive inhibitor of herpes virus DNA polymerase • Incorporates into and terminates growing viral DNA chain • Dose = 5 mg/kg q8h for mucocutaneous HSV • t½ = 3 hours • Renally excreted • CrCl 25-50 mL/min: dose q12h • CrCl 10-25 mL/min: dose q24h • CrCl < 10 mL/min: 50% of dose q24h

17. Clinical Question

18. Literature Search

19. 2009

20. Cochrane 2009

21. Cochrane 2009Acyclovir Prophylaxis • 15 RCTs included in the prevention outcome • 11 trials evaluated acyclovir vs. placebo

22. HSV Oral Lesions (Route)Acyclovir vs. Placebo NNT 3

23. HSV Oral Lesions (Age)Acyclovir vs. Placebo NNT 3

24. Adverse Events • Reported in 9 trials • Evaluated rash, neurological impairment, renal and hepatic impairment • None of the trials reported a statistically significant difference in the presence or number of adverse events according to active agent

25. Author’s Conclusions • “There is evidence of a significant difference in efficacy between acyclovir administered orally or intravenously and placebo for prevention measured by oral lesions”

26. Limitations • RCTs included were patients with hematological malignancies • Not generalizable to our patient • Unknown whether 2 trials in HSV oral lesions outcome were HSV + lesions • Overall risk of bias was unknown in all studies • 11 trials in prevention outcome had uncertain risk of bias • 2 trials in prevention outcome had high risk of bias • Couldn’t determine if publication bias was present due to too few trials

27. Application • Necessary • JM already has experienced an episode of HSV reactivation leading to severe oral mucositis and is still recovering from it • JM will be receiving another cycle of chemotherapy with the same agents • Effective • Evidence that acyclovir may be beneficial for prevention of HSV oral lesions • Safety • No differences in rates of adverse events found vs. placebo in trials • JM not receiving any other nephrotoxic medications • Adherence • IV formulation will allow JM to receive therapy

28. Therapeutic Plan • Initiate acyclovir 325 mg IV q12h until neutropenia and mucositis resolve • Discontinue heparin 5000 units SC q12h • Suggested decreasing pantoprazole to 40 mg IV daily • Continue monitoring breakthrough doses of hydromorphone outside of nursing care doses

29. Monitoring Plan

30. Course To Date • Acyclovir 325 mg IV q12h initiated • Ceftriaxone discontinued • Watchful waiting for febrile neutropenia • June 5-7th received chemotherapy • 50% etoposide dose • 75% cisplatin dose • June 8th received filgastrim 480 mcg SC x 2 days • neutrophil count increased to 42.87 • June 11th counts: WBC 20.8, neut 20.5, plts 132 (↓ from 352 prior to chemo) • Still passing blood per rectum daily

31. Questions?