Orolabial Herpes Simplex Old Disease: New Treatments Relevant Conflict of Interest Disclosure Advisory Board with honorarium: Cipher Ted Rosen, MD Professor of Dermatology Baylor College of Medicine Houston, Texas Orolabial Herpes: Fast Facts WHO: 60 95% world s population is infected with at least one herpesvirus Bull WHO 63:185, 1985 HSV 1 mostly nonsexual transmission; closely associated w/ orolabial and facial disease (may be elsewhere) Primary infection followed by latency; Latency in.. Dorsal root ganglion and oral mucosa, possibly in keratinocytes ASx shedding (1 25% of days) or periodic clinical recurrences Clin Infect Dis 30:261, 2000 Seroprevalence studies HSV 1 positivity (USA) >50 years old 75 85+% 40 49 years old 65.3% 20 40 years old 57.7% 14 19 years old 39.0% Semin Dermatol 11:2002, 1992 JAMA 296:964, 2006 Epidemiology Caucasian Females Orolabial Herpes Orolabial Herpes: Fast Facts Most common manifestation of HSV 1: Recurrent lesions Common vernacular: cold sores or fever blisters Morphology: grouped vesicles, tender or painful, associated swelling and possibly lymphadenopathy How many of those who are seropositive experience recurrent lesions? Guess estimate: 15 40% CMAJ 113:627, 1975 Am J Clin Dermatol 3:475, 2002 J Am Acad Dermatol 57:737, 2007 Frequency of recurrences varies: every other week to every 5 10 years Herpes 9:64, 2002 Severity of recurrences varies widely Generally self limiting in normal host to 12 17 days J Infect Dis 161:191, 1990 Resolves without sequelae; but some risk of scarring Orolabial Herpes: Fast Facts Potential stimuli for recurrences Emotional stress Infection, usually URI Ultraviolet light exposure Physical fatigue Local trauma Menses Immunosuppression Dermatol Clin. 20:249-66, 2002 1
Smoking associated w/ less frequent and less severe recurrent HSV1 Acta Odontol Scand. 48:119, 1990 Clinic Dermatol. 16:641, 1998 Orolabial Herpes: Clinical Progression Prodrome: pain, burning, itching, tingling Lasts about 6 hours; ¼ recurrences abort Erythema Papule formation Vesicle formation (Few hours from onset) Ulcer soft crust Crust formation (72 96 hours from onset) Residual: mild erythema, flaking, swelling WHY IS THIS SEQUENCE IMPORTANT? Early intervention! Short Rx window! J Infect Dis 161:185, 1990 Stages Herpes Simplex Labialis Stages Herpes Simplex Labialis 3-4 Days 7-14 Days 3-4 Days 7-14 Days Non-Ulcerative Ulcerative Recurrence Resolution Normal Skin Non-Ulcerative Ulcerative Recurrence Resolution Normal Skin Viral replication in reservoir tissue Viral replication in reservoir tissue J Infect Dis. 194 Suppl 1:S11-8, 2006 J Infect Dis. 194 Suppl 1:S11-8, 2006 Non-Ulcerative 8-12 hours Viral replication in reservoir tissue Stages Herpes Simplex Labialis 3-4 Days 7-14 Days Ulcerative Recurrence Resolution Normal Skin Why Bother Treating? Reduce discomfort Reduce cosmetic disfigurement Speed healing Decrease transmission risk Reduce scarring risk Lower emotional distress Reduce recurrence frequency? Reduce recurrence severity? J Infect Dis. 194 Suppl 1:S11-8, 2006 2
Why Bother Treating? Oh no! A cold sore! No way Reduce discomfort Reduce cosmetic disfigurement Speed healing Decrease transmission risk Reduce scarring risk Lower emotional distress Reduce recurrence frequency? Reduce recurrence severity? Therapeutic Decisions: Recurrent HSV 1 Episodic therapy Continuous suppression Therapeutic Decisions: Recurrent HSV 1 Episodic therapy Topical Oral Muco adhesive Continuous suppression Therapeutic Decisions: Recurrent HSV 1 Episodic therapy Topical Oral Muco adhesive Continuous suppression Oral Anti HSV Drugs Acyclovir Penciclovir 3
Acyclovir vrs Penciclovir It all evens out in the end Penciclovir has higher affinity for HSV thymidine kinase compared to acyclovir Penciclovir has prolonged intracellular half life (10 20x longer) vrs acyclovir Triphosphorylated penciclovir has lower affinity for HSV DNA polymerase Triphosphorylated penciclovir binds to DNA polymerase reversibly Episodic versus Suppressive Therapy It is estimated that less than 10% of recurrent orolabial herpes patients have disease of such frequency and/or severity to warrant chronic suppressive anti viral therapy Antiviral Chem Chemother 4(Suppl 1):3, 1993 JAMA 277:1374, 1997 Clin Microbiol Rev 16:114, 2003 N Engl J Med 297:69, 1977 Oral Surg Oral Med Oral Pathol Oral Radiol Endod 103(Suppl 12):1, 2007 Arch Int Med 168:1137, 2008 Episodic Rx Seems Reasonable Suppressive Rx Seems Reasonable Topical Rx Seems Reasonable Oral Rx Seems Reasonable 4
Systemic Rx: Intravenous? Acyclovir 15mg/kg 5x daily x 7 days Cancer HIV/AIDS Systematic analysis: oral valacyclovir 1g BID x 7 days works just as well as IV acyclovir in immunocompromised Cochrane Data Systm Rev 2009; 1 Art #CD006706 Episodic v. Suppressive Infrequent outbreaks: Episodic Mild Moderate severity: Episodic Very frequent: Suppressive Very severe: Suppressive Eczema (self/child): Suppressive! EM associated: Suppressive! Surgery, Sunburn: Prophylactic suppression No prodrome: Suppressive? (If desired) Patient preference: Either This is the third time I got fever blisters and a rash! Recurrent Erythema Multiforme J Am Acad Dermatol 71(4):e146-7, 2014 J Am Acad Dermatol 62:45 53, 2010 Why Topical Therapy? Few real or potential side effects No drug drug interactions to consider No long term health concerns Easily portable, easily started quickly Directed therapy: onto the pathology Patient empowerment Makes sense: wound healing Cost effective It works.sometimes Unka Teddy s Quote: The fewer pills you take in life, the better off you are. For many patients, topical therapy for orolabial herpes is sufficient and equivalent to episodic oral therapy. The choice should be on patient by patient basis. 5
What To Measure? Not all studies done in the same way! Dx by history + culture, culture, viewing Outbreaks monitored by viewing, diary Lesions measured, or not Cultures done, or not Drug compliance considered, or not End points: time to loss of hard crust or time to complete healing. Others: loss of pain, negative culture, size Topical Agent Time Decrease in resolution time Decrease in pain duration Acyclovir 0.5-2.0 days None Penciclovir 0.7-1.2 days 0.6-1.0 day Docosanol 0.75-1.6 days 0.56 day Acyclovir-HC 1.4 days 1 day Miscellaneous Vehicle type critical to Rx success OK to apply later (papule) Increase in attacks that are aborted Fewer lesions progress to ulceration Arch Intern Med 2008;168:1137 Acyclovir 5% + Hydrocortisone 1% Approved: 2009 Applied 5x daily for 5 days, starting at prodrome if possible Reduced percent ulcerated: 58% v 74% Reduced time to healing: 1.4 days Reduced lesion size: 78 v 155 mm 2 Reduced duration pain: 1 day Well tolerated; No major AEs No TK mutations or acyclovir resistance Antimicrob Agents Chemother 46:1870, 2002 Postgrad Med 122:1, 2010 J Am Acad Dermatol 64:696, 2011 Pediatr Dermatol 29:105, 2012 Antimicrob Agents Chemother 58:1273, 2014 An Acad Bras Cienc 87(2 Suppl):s1415 20, 2015 New Local Therapy Muco adhesive acyclovir 50mg Muco adhesive Acyclovir Muco adhesive Acyclovir Applied at prodrome* Single tablet is therapy Massive concentration labial mucosa/saliva Reduces healing time (v. placebo) by ½ day Reduces duration of episode by 1.0 day Compared to placebo, 24% more episodes are aborted (no lesions develop): 35% overall?disease modifying agent; During 9 month follow up, increased time to next recurrence by 105 days (mean) or 40 days (median) J Drugs Dermatol. 13:791-8, 2014 Expert Rev Anti Infect Ther. 12:283-7, 2014 J Clin Pharmacol & Clin Pharmacokinet. 2014; 1(1):000001 6
Disease Modification? Time to next recurrence, Days 350 300 250 200 150 100 50 0 Recurrence (9-Month Follow Up) (n=537) 304 (days) Mucoadhesive Sitavig Acyclovir +105 Days p= 0.041 199 (days) placebo J Drugs Dermatol. 2016 Jun 1;15(6):775-7 23 yo Hispanic grad student Part time medical reception 10 year hx oro labial HSV HSV 1 (culture proven) Detailed diary of attacks: 37 68 days apart (5 yrs) Abreva and Denavir used Anything better? Given Muco adhesive acyclovir 44 days after presentation, outbreak and applies Sitavig NEXT episode 142 days later Subsequent episodes occured at six, now every nine months Not a cure Disease modifying drug due to increased interval between prodromes (and/or attacks) J Drugs Dermatol. 2016 Jun 1;15(6):775-7 J Drugs Dermatol. 2016 Jun 1;15(6):775-7 Why Systemic (Oral) Therapy? Availability of multiple agents Various agents all efficacious All agents very safe Almost no drug drug interactions Several agents with convenient short course regimens Generics now available, lower cost Which Oral Agent? Generic since 1990 200 mg, 400 mg, 800mg Generic since 2009 500 mg, 1000mg Generic since 2007 125 mg, 250 mg, 500 mg 7
Oral Episodic Therapy Oral Agent Time Acyclovir 400mg 5x/5d Valacyclovir 2gm x 2, 1d Famciclovir 1.5gm x 1 Decrease in resolution time 1.0 day 1.0 day 1.0 day Increase in aborted lesion 14% > placebo 10-22% > placebo 2.4-15.4% > placebo Miscellaneous Must Rx within 48 hours Not approved Must Rx within 48 hours FDA-approved Must Rx within 48 hours FDA-approved Chronic Suppressive Therapy? Acta Derm Venereol 90:122, 2010 Evid B Dent 9:117, 2008 Arch Intern Med 168:1137, 2008 J Antimicrob Chemother 53:703, 2004 Key Points Agent Dose Decreased number of overt outbreaks Time studied Miscellaneous No drug regimen is FDA approved for chronic suppression of HSV1 orolabial herpes HSV1 does not suppress as easily as HSV2 does, and therefore benefit is not as great Acyclovir 400mg BID Valacyclovir 500mg-1g/QD Famciclovir 500mg BID Max 53% (RTC) Max 50% (RTC) Data very soft 4 mo 4 mo Short term Not FDA Approved Not FDA Approved Not FDA Approved J Evid Based Dent Pract. 2013;13:16 Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:618 Arch Intern Med 2008;168:1137 J Drugs Dermatol 2007;6:400 Cutis 2003;71:239 Derm Surg 1999;25:242 Cochrane Database Syst Rev. 2015 Aug 7;(8):CD010095 Off Beaten Path Thoughts The long term use of oral antiviral agents can prevent HSL, but the clinical benefit is small. 8
Acyclovir Resistant HSV? Mild: Trifluridine ophthalmic soln Acyclovir Resistant HSV? Mild: Trifluridine ophthalmic soln Severe enough to warrant major Rx IV Foscarnet IV Vidarabine IV Cidofovir Topical Cidofovir 1 3% IL Cidofovir High Potency Combo Rx (Episodic) Valacyclovir 2g BID x 1 day PLUS Clobetasol 0.05% gel BID x 3 days Decreased healing time to 5.8 d total Herpotherm (aka HotKiss ) Local thermotherapy 50-53 0 C for 4 seconds Applied 1-5x daily J Eur Acad Dermatol Venereol 23:263, 2009 Approved device in UK, EU, Australia, Canada, several Latin American countries; Not approved in USA, but available on either E Bay or Amazon Heat v. Acyclovir Heat versus Acyclovir Clin Cosmet Investig Dermatol. 6: 263 271, 2013 Clin Cosmet Investig Dermatol. 6: 263 271, 2013 9
Remission of Labial HSV? Recurrent orolabial herpes, resistant to chronic suppressive Rx (8 10 outbreaks/yr) Imiquimod: specific immune upregulation 62.5mg of 5% imiquimod applied under occlusion to lesion free abdominal skin QHS during outbreak (1/4 of a sachet/dose) 3 weeks total duration of imiquimod therapy During Rx: decreased Sx & healing time (3d) After Rx: 21 months NO outbreaks (v. 18 prior) Sustained increase: CD4+, CD8+, IFN gamma Ted Rosen, MD Antivir Therapy 16:863-69, 2011 Thanks for your attention! Ted Rosen, MD Baylor College of Medicine Houston, Texas 10