Acyclovir for the Prevention of Herpes Simplex Mucositis During Chemotherapy

Sukhjinder SidhuInterior Health Pharmacy Resident

Critical Care RotationJune 12, 2014

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

Our PatientID JM – 43 y.o. male (72 kg; 180 cm; BMI 22.2 kg/m2)

Admitted April 24th to PRH and transferred to KGH ICU May 10th

CC Altered level of consciousness and confusion• Gradual deterioration in health over last several mo.• Not eating well – weight loss of ~20 lbs• Swelling in legs • Scrotal swelling

Allergies NKDASocial Hx Ø

PMHx Ø

MPTA Vitamin D, Vitamin B Complex, Serrapeptase, Lysine, Bromelain, ASA, Ranitidine, Ibuprofen

Review of Systems - PRHVitals T 33 HR 120-130 at times SBP 140

CNS/Neuro Ø following commands, Ø purposeful movements

HEENT Cachectic

RESP Kussmaul breathing

CVS JVP flat, Troponin 0.73

GI Palpable masses in LUQ and LLQLactic acid 4.2 LFTs WNL except ALP 169 LDH 7162 CK 220

GU Large mass in scrotumUrea 55.1 Cr 757 GFR 7

ENDO Glu 3.4

MSK/Derm Bilateral leg edema with numerous superficial but indurated skin ulcersCHEM Na 133 K 6.6 CO2 < 5 AG NR Ca 2.43 PO4 5.84 Mg 1.45

HEME WBC 23.9 neut 23.18 Hgb 80 plt 720 INR 1.1

VBG pH < 6.80 PaCO2 12 HCO3 NR

Course in Hospital - PRHApril 24 Intubated and dialyzed in PRH ICU

April 25 18 cm cystic mass and solid scrotal mass on imaging consistent with malignancyRetroperitoneal masses measuring 15 and 19 cmHydronephrosis due to bilateral ureteric compression

April 28 ExtubatedApril 30 Left radial orchidectomy, cystoscopy, insertion of bilateral ureteric stents

May 4 Debridement of necrotizing soft tissue disease on left thigh, left lower leg, right groin, distal right legPassed large volumes of clot and some fresh blood per rectum requiring multiple blood transfusions

May 7 Colonoscopy – entire colon severely inflamed with pseudopolyps; deep ulcer in rectum with an adherent clot

May 9 Planned transport to VGH Plastic Surgery Service for skin grafting of leg ulcers & assessment by Oncology

May 10 SBP ↓ to 60, Hgb ↓ 65 (from 101) – resuscitated with 8 units PRBCs, 2 units FFPSigmoidoscope showed bleeding ulcer that was clipped/epinephrine Transferred to KGH ICU

Review of Systems - KGHVitals T 36.9 HR 98 BP 98/45 RR 28 O2 sat 93% (RA)

CNS/Neuro A&O x 3

HEENT Swollen gingiva; red, swollen tongue; left upper lip ulcer

RESP Ø

CVS Gross edemaTrop 0.07

GI Albumin 12 lactic acid 1.2

GU Edematous scrotum; abdominal incisionsUrea 23.5, Cr 404, eGFR 14

ENDO Glu 3.7 TSH 9.22 T4 9.4

MSK/Derm Leg ulcersCHEM Na 132 K 4.5 CO2 7 AG 12 Ca 1.85 PO4 2.59 Mg 0.77

HEME WBC 9.9 neut 9.3 Hgb 124 plts 105 INR 1.1

MicrobiologyDate Site Organism Susceptibility

April 25 L Thigh Ulcer +1 Group B Strep S – penicillin, clindamycinL Lower Leg Ulcer +2 Group B Strep

+2 GN rodsS – penicillin, clindamycin

Blood ØApril 28 Sputum (ETT) +1 Candida albicansMay 4 L Leg Wound +1 E. coli R – cephalexin; S – pens, cipro,

gent, septra, cefazolin, ceftriax

May 11 R Leg Wound +3 Candida albicans+3 VRE faecium R – linezolid; S – dapto

L Leg Wound +2 Candida albicans+2 VRE faecium+1 GN bacilli

R – linezolid; S - dapto

May 20 Blood K. pneumoniae R – cipro, S – ceftriax, gent, tobra, septra, pip/tazo

May 27 Blood Ø

Course in Hospital - KGHMay 10 Admitted to KGH ICUMay 11 Continues to receive colonoscopies PRN with arterial clipping, Hemospray and PRBCs PRN

Initiated on ciprofloxacin and fluconazoleMay 12 Started chemotherapy with cisplatin & etoposide for curative intent (5 days x 4 cycles) WBC 5.9,

neut 5.4Reinstituted CRRT due to anasarca

May 15 Started developing mouth soresMay 16 CRRT discontinued and chemotherapy cycle completedMay 19 Neutropenia – 0.38; WBC 0.5

Initiated on daptomycin and metrondizaole; continue cipro and fluconazoleMay 20 Septic shockMay 23 ABX broadened – D/C cipro and started on meropenemMay 25 Atrial fibrillation

Filgrastim initiated x 3 daysMay 26 Re-intubated for airway protection secondary to increased secretions

Mouth swab +ve for HSV type 1; corneal ulcerations –acyclovir and trifluridine eye drops initiatedMay 28 Neutropenia resolvedMay 30 ABX narrowed – D/C dapto, fluconazole, meropenem and start ceftriaxoneMay 31 Tracheotomy; atrial fibrillation resolved

Current Problems & MedicationsJune 3

Indication Medication

Lower GI bleed/SuPx Pantoprazole 40 mg IV q12h

Pain 20 to mucositis Hydromorphone 0.2 mg/hr + hydromorphone prn

Bacteremia 20 to K. pneum Ceftriaxone 2 g IV daily

High-risk of severe HSV mucositis recurrence

Ø

Corneal ulcerations Trifluridine 1% i gtt into right eye 5x day

Testicular cancer Cisplatin and etoposide to begin June 5

DVT prophylaxis Heparin 5000 units SC q12h

AKI Ø

Nutrition TPN

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 etoposide chemotherapy secondary to decreased renal function

• JM may require filgrastim prophylaxis secondary to neutropenia experienced during first cycle of chemotherapy

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

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

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

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

Therapeutic Approach

• Watchful waiting and initiate antivirals if mucositis worsens

• Oral valacyclovir• Oral acyclovir• Parenteral acyclovir

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

Clinical QuestionP In a male patient with recent re-activation of HSV1 mucositis following

chemotherapyI Acyclovir prophylaxis

C Placebo

O Prevent the occurrence of HSV infections Ø Increased risk of adverse events

Literature SearchDatabases PubMed, Embase, Google Scholar

Search Terms Acyclovir, herpes labialis, stomatitis, prevention, neoplasms

Limits Ø

Results Multiple RCTs in HSCT transplants/leukemias1 Cochrane Review

2009

Cochrane 2009Design Meta-analysis

Objective Effects of interventions for the prevention or treatment of herpes simplex virus in patients receiving treatment for cancer

Databases searched CENTRAL, MEDLINE, EMBASE, CINAHL, CANCERLIT, SIGLE, LILACS, controlled trials database

Selection criteria RCTs

Included patients Anyone receiving treatment for cancer (adult or child)

Intervention Any agent prescribed prophylactically or therapeutically for orofacial lesions caused by herpes simplex virus

Comparator Placebo, no treatment, or any other active intervention

Outcome Primary• PREVENTION: Presence/absence of clinical/culture positive (with or

without clinical symptoms) herpes simplex virus infections• TREATMENT: Time to complete healing of lesionsSecondary• Duration of viral shedding, recurrence of lesions, time to relief of pain,

amount of analgesia, days of stay in hospital, cost of oral care, patient quality of life, adverse effects

Cochrane 2009Acyclovir Prophylaxis

• 15 RCTs included in the prevention outcome – 11 trials evaluated acyclovir vs. placebo

Characteristic Range

Year of study 1983-1995

Number of participants 21 – 107

Type of participants 2 – 84 years old with cancer (majority of trials recruited patients with hematological malignancies)

Acyclovir dosage PO: 200 mg – 800 mg QIDIV: 250 mg/m2 q12h OR 5 mg/kg IV q8h, followed by PO

Duration of treatment 8 days prior to chemotherapy – 6 months post

HSV Oral Lesions (Route)Acyclovir vs. Placebo

NNT 3

HSV Oral Lesions (Age)Acyclovir vs. Placebo

NNT 3

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

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”

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

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

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

Monitoring Plan

Efficacy Toxicity

CNS Controlled or improvement in pain Malaise, headache, lightheadednessHEENT Resolution or no further progression of

oral lesionsCVS HR < 100GI Ability to swallow fluids/meds Nausea, vomiting, ↑ LFTsGU ↑ SrCrMSK/DERM Rash

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

Questions?