HPV Genital Warts Treatment Tables of Evidence

Genital Warts Treatment Author/Citation Description of Study Population, Sample Size Outcome Summary Points Komericki P et al, 2011 Randomized, open label trial 51 Austrian, Complete clearance at the end  Clearance of baseline of imiquimod 5% cream vs immunocompetant, adult, of treatment period (5 weeks warts was statistically podophyllotoxin 0.5% non-pregnant pts were after start of podophyllotoxin identical in the two solution randomized (excluded if and 16 weeks after start of interventions (72% warts were judged large imiquimod) podophyllotoxin and enough to warrant removal using an intention to treat 75% imiquimod) with surgical excision) analysis  No statistically 45 pts (7 women, 35 men) significant difference in completed the intervention. Side effects, assessed at 2 side effects, most Imiquimod 5% was applied week intervals throughout common local reaction 3x/week until warts cleared therapy was or up to 16 weeks, erythema/inflammation podophyllotoxin 0.5% was (in 37.8% of all pts) applied 2x/day on 3 consecutive days until warts cleared or up to 4 weeks Zervoudis S et al, 2010 Randomized, evaluator- 62 Greek women with EGW Clearance  Complete clearance blinded trial of laser and perianal warts, excluded Clinical recurrence at 10 occurred in 67% of those treatment of EGW alone vs if pregnant and if the warts week intervals up to 6 months treated with laser alone, laser treatment followed by had ever been treated before. after laser procedure and in 81% of those pidotimod (also known as All pts treated with CO2 laser Adverse events treated with laser plus Polimod, an immune vaporization to all of their pidotimod (not stimulator) plus oral vitamin lesions. Then pts were statistically significant) C randomized to no further  No recurrences in 6 therapy or to applied months of follow-up pidotimod 2 sachets per day among those who cleared and took oral vitamin C  One adverse event 1000mg per day for 15 days, reported in the laser plus followed by pidotimod 1 treatment group – nausea sachet per day and vitamin C on the second day of 500 mg per day for another treatment 60 days. Gilson R et al, 2009 Randomized, double-blind 140 pts aged 18–70, with Complete clearance using  Complete clearance at 4 trial of weekly cryotherapy perianal or EGW totaling at intention to treat analysis and 12 wks was higher in plus placebo versus weekly least 1cm2, not treatment in Recurrence the cryo +

cryotherapy plus the last 4 months, Adverse effects podophyllotoxin group podophyllotoxin 0.15% investigators had to believe (60% and 60%) than in cream pts could be treated with cryo the cryo alone group or podophyllotoxin plus cryo. (45.7% and 45.7%) but All pts received weekly not statistically cryotherapy for 45s freeze, significant. then the next day started  No difference in groups placebo or podophyllotoxin by 24 weeks of follow up 0.15% cream 2x/day for 3 (68.6% and 64.3%) consecutive days, repeated  More pts discontinued weekly for up to 4 weeks or use of the cream in the until complete clearance. podophyllotoxin group Cryo was repeated weekly for than the placebo group up to 12 weeks or until (18.6% vs 5.7%) complete clearance. Mi X et al, 2011 Randomized, double blinded, 109 pts, aged 18–54 years, Complete clearance by site of Complete clearance after 2 placebo controlled trial of immunocompetant, non- wart treatments cryotherapy plus placebo and pregnant and without internal Recurrence at 12 weeks  Overall complete PDT vs cryotherapy plus warts, with perianal or genital Adverse events response better in the ALA and PDT warts, were randomized. All combination therapy pts received cryotherapy, an 8 group (70.4% vs 42.4%) sec freeze to each wart twice.  The same (32.4% vs Immediately following 32.6%) for both cryotherapy, the pts treatments for perianal randomized to cryo + ALA warts and PDT had their warts  Combination therapy was treated with 20% ALA superior (100% vs 54%) solution for 3 hrs. The for the urethral meatus placebo group received sterile  Combination therapy was saline soaked gauze for 3 hrs. superior for other All pts then had their warts external genital warts irradiated with a 635nm laser (94.2% vs 50.5%) emitting 100J/cm2 for  Recurrence rates after 12 100mW/cm2. If lesions did wks were less with not clear, the treatment was combination therapy repeated in 7 days. overall (12.5% vs 32.2%)  100% of the pts in both

groups had at least mild side effects, including pain, crusting, erosions, but no one withdrew from the study due to side effects. Liang et al, 2009 Randomized trial of PDT 90 adult, non-pregnant, Clearance  96% complete clearance w/ALA or CO2 laser Chinese pts with distal Recurrence at 12 weeks after after 3 treatments in PDT urethra or GW were last treatment group randomized to PDT w/ ALA Adverse events  100% complete clearance (67pts) or CO2 laser (23 pts). after 3 treatments in CO2 Pts received either 20% ALA laser group solution applied for 3 hrs,  Recurrence rate was followed by PDT with 632 significantly lower with nm at 100J/cm2 at 100mW, the PDT group vs the or had 2% topical lidocaine CO2 group (9.4% vs applied followed by CO2 17.4%) laser treatment to all the  Adverse events were all lesions. Pts were examined mild, but significantly one week following therapy, lower in the PDT group and any pts with residual compared to the CO2 disease had a repeat group (9% vs 100%) treatment, for up to 3 total treatments. Yang J et al, 2009 Systematic review with meta- 12 trials including 1445 pts. 7 Risk of complete response  Complete response more analysis of interferon therapy trials of local INF vs placebo, likely with local IFN versus others 5 of systemic INF vs placebo than placebo (combined RR 2.68, 1.79–4.02 P<0.01)  No statistical differences between systemic INF and placebo for complete response  No differences in risk of relapse between local or systemic INF and placebo

Question: Treatment Modalities: 5-FU Efficacy

Author/Citation Description of Study Population, Sample Size Outcome Summary Points Weisman et al, 1982 Randomized, controlled trial 59 immunocompetant adults Complete response/cure and 5-FU + salicylic acid group: of 0.5% 5-FU and salicylic (30 men and 29 women) with median time to cure  Cured – 18 pts acid varnish vs “placebo” GW were randomized. 30 (60%) Median (article in German, abstract in (salicylic acid varnish without received 0.5% 5-FU and Partial response treatment time English) the 5-FU) salicylic acid varnish and 29 before cure was 2 received salicylic acid varnish “Blood tests” (not further wks in men, 3 wks in without the 5-FU. specified in the English women abstract) before and after  Partial response - 6 Within both randomized therapy pts (20%) groups, women were treated  No response – 6 pts 2x/week in the clinic and men Patch tests to 5-FU after (20%) self-treated daily at home. therapy Salicyclic acid varnish alone group:  Cured – 8 pts (28%) Median time to cure was 2.5 weeks for men and 3.5 weeks for women  Partial response – 4 pts (14%)  No response -17 pts (59%)

5-FU + sal acid was superior in producing cure when compared to sal acid alone (P < 0.01)

Blood tests were the same (and normal) before and after therapy in all patients

Patch testing after therapy revealed no sensitization Botacini et al, 1993 Randomized, controlled trial 74 immunocompetant women Complete response/cure 5-FU group: of 5% 5-FU cream vs placebo with GW received 5% 5-FU  Cured – 52 pts (article and abstract available vs podophyllin 2% and 4% cream, Partial response (70%) only in Portuguese, some 16 - placebo  Partial response - 7 translation done through podophyllin 2% - 5 pts pts (10%) Google translate) podophyllin 4% - 40 pts  No response – 55 pts (20%) Placebo group:  Cured – 5 pts (31%)  Partial response – 1 pts (6%)  No response - 10 pts (62%) Podophyllin 4% group:  Cured – 3 pts (60%)  Partial response - 1 pts (20%)  No response – 1 pts (20%) Podophyllin 2% group:  Cured – 19 pts (48%)  Partial response – 5 pts (12%)  No response - 16 pts (40%) Syed et al, 2000 Randomized, controlled-trial 30 adult immunocompetant Cure at 4 weeks after starting 5-FU 1% gel group: of intravaginal 5-FU 1% gel women with intravaginal GW treatment  Cured – 25 pts (83%) received 5-FU 1% gel, 30  Adverse events – 2 pts received placebo Adverse events (7%)  Recurrence – 2 pts (7%) Placebo group:  Cured – 4 pts (13%)  Adverse events – 1 pts (3%)

 Recurrence – 1 pts (3%)

Wallin et al, 1977 Randomized, controlled trial 42 adult, immunocompetant Cure at 4 weeks 5-FU group: of 5% 5-FU cream vs men with GWs who had not Withdrawals  Cured at 4 weeks– 10/18 podophyllin 25% gel received any treatment in the Side effects who finished therapy previous 6 months were (55%) randomized to  •Withdrawals – 2 pts 5% 5-FU cream (20 pts) (10%) applied every night for 2  Erosions at treatment weeks or area reported in 10 (55%, podophyllin 25% gel applied median time to erosions by a physician once per week, 10 days of treatment) then washed off 4-6 hrs later, Podophyllin 25% group: for 4 weeks (22 pts).  Cured at 4 weeks – 11/19 who finished therapy (58%)  Withdrawals – 3 pts (14%)  Erosions at the glans penis reported in 1 pt (5%) Authors concluded that there were no differences in efficacy between the 2 therapies Batista C et al, 2010 Cochrane review; meta- Trials of 5-fluorouracil (5-  5FU presented better risk analysis (Summary of the FU) versus placebo or other of cure than: placebo above 5 studies plus other treatments for safety and (RR 0.39 (0.23–0.67) studies comparing 5-FU alone efficacy against EGW meta-cresol-sulfonic acid to meta-cresol-sulfonic acid, through August of 2009. 6 (MCSA) (RR 2.11 (0.83– 5-FU + CO2 laser, and 5FU + trials, including 645 women 5.37) or podophyllin 2,4, IFN and 343 men, were found. All or 25% (RR 1.26 (0.86– pts were aged ≥18 years and 1.82) non-immunocompromised.  5FU alone had no statistical difference for failure versus 5FU+ CO2 laser (RR 0.69 (0.43–

1.11) or 5FU +IFN alpha 2A (low dose) (RR 1.02 (0.87–1.119)  5FU alone had higher risk of failure when compared to 5FU + INF alpha2A (high dose) (RR 10.78 (1.50–77.36) and 5FU + CO2 laser +INF alpha 2A (high dose) (RR 7.97 (2.87–22.13)

Question: Treatment Modalities: Sinecatechins – Efficacy

Author/Citation Description of Study Population, Sample Size Outcome Summary Points Tatti S et al, 2010 Pooled analysis of 2 401 pts treated with Complete clearance  OR for complete randomized, controlled, polyphenon E 10% ointment Recurrence clearance with double blind clinical trials of and 207 pts treated with Adverse events polyphenon E 10% polyphenon E 10% ointment vehicle in two 16-week phase ointment vs vehicle was vs vehicle III studies in adult pts with 2.10 (1.485–2.976) in (Pooled analysis of 2 pivotal EGW and perianal warts. intention to treat analysis trials by Stockfleth et al and (56.3% cleared in Tatti et al that were published treatment group vs in 2008 and demonstrated 35.4% cleared in the efficacy and safety) vehicle group)  Gender subgroup analysis showed polyphenon to be more effective in complete clearance for both men and women  Among pts who were clear at 16 wks, there was no difference in recurrence rates 12 weeks later (6.5% vs

5.8%)  Only 1 pt receiving polyphenon had a serious AE related to treatment; pustule vulvovaginitis  7.0% of the treatment group and 2.4% of the vehicle group reported treatment-related adverse events. Tzellos T et al, 2010 Meta-analysis of the 3 2 independent reviewers Expressed as risk ratios:  RR clearance of baseline randomized, placebo- searched Medline, EMBASE, -Clearance of baseline warts warts with 15% ointment controlled, double blinded Med, Web of Science, with 15% ointment and 10% 1.53 (95% CI 1.29–1.82) studies (Gross et al, Cochran data search through ointment/cream  RR clearance of baseline Stockfleth et al, and Tatti et Feb 2010, identified 3 -Clearance of baseline warts warts and new warts with al) randomized placebo- and new warts with 15% 15% ointment 1.45 controlled trials of ointment and 10% (1.21–1.74) polyphenon E 15% and 10% ointment/cream  RR clearance of baseline for treatment of GW. Adverse reactions warts with 10% Trial were of high quality and ointment/cream 1.46 included: 660 men, 587 (1.23–1.74) women  RR clearance of baseline warts and new warts with 10% ointment/cream 1.42 (1.19–1.70)  Local skin signs and symptoms were mostly mild, no statistical analyses performed

Question: Treatment Modalities: Imiquimod 5% – Efficacy

Author/Citation Description of Study Population, Sample Size Outcome Summary Points Greensill A et al, 2012 Case series 50 British adolescent pts Clearance  45 pts completed, 5 pts (aged 13–17 yrs) treated with Recurrence could not tolerate

imiquimod, 40 girls, 10 boys, Adverse events (?maybe due to 3 diabetics, 5 pts were Rxd erythema/irritation? Not with TCA or cryo at the same clear) time.  Of 45 who completed therapy, 66% full clearance in <2 months, and 86% full clearance in <6 months  3 recurrences of 45 – at 9, 18, and 36 months after Rx completed Masuko T et al, 2011 Case report 28 month old Japanese girl Clearance  Response at 2 weeks, with perianal warts, treated Recurrence complete clearance at 7 with imiquimod 5% cream, 3 Adverse events weeks x/week overnight until  No recurrence 4 weeks complete clearance. after complete clearance  “Inflammatory response” was the only adverse event noted Brandt H et al, 2010 Case series 4 Brazilian children (aged 1– Clearance  2 cases resolved 2 years) with perianal and Recurrence completely after 3 weeks GWs. One previously treated Adverse events of treatment with podophyllin. All treated  2 cases resolved with imiquimod 3x/week. completely after 4 weeks Treatment continued for a of treatment total of 6 weeks in all cases.  1 case had moderate erythema on treated skin; no other AEs  No recurrences 6 months after treatment stopped

Question: Treatment Modalities: Imiquimod 5% – Safety, adverse events

Author/Citation Description of Study Population, Sample Size Outcome Summary Points Kumar B et al, 2011 Case series 22 immunocompetant Indian Complete resolution  Complete resolution in men with GW applied Adverse events 54% (time frame not imiquimod 5% cream 2x/day defined)

for 3 days per week up to 24  27.3% had local adverse weeks. reactions, most after 2 wks of treatment  1 pt had severe irritation at 7 weeks, then developed vitiligo of the treated area that lasted for 7 months  45.5% of pts reported belching and epigastric discomfort at some point during therapy  36.6% of pts reported fever, myalgias, fatigue or headache at some point during therapy  1 pt developed erythema multiforme of the palms and oral mucosa 2 wks after starting imiquimod (no HSV testing done, pt had h/o oral HSV) Anadkat M et al, 2011 Case report 43 yo American man with Clearance  Mild improvement in HIV, Burkitt’s lymphoma in Adverse events warts remission, treated for 5 penile  Mild irritation at the site genital warts with monthly of application cryotherapy and 3x/week  After 3 months of imiquimod 5% cream. imiquimod Rx, had a PET scan for routine surveillance of his lymphoma which showed inguinal adenopathy and uptake, repeat scan four months later had increased adenopathy, so he had a biopsy that revealed reactive

changes. Imiquimod was then stopped, cryotherapy every 4 weeks continued, and 2 months after the imiquimod was stopped the PET was repeated and the adenopathy had resolved. O’Mahony C et al, 2010 Case series One pt, 37 yo uncircumcised  Possible association of man with lesions on penis lichen sclerosis after 3 genital warts vs lichen wks of imiquimod sclerosis, bx more c/w GW, therapy to the penis in 1 treated with imiquimod 5% pt (application schedule not  Possible association of reported) after 3 wks, lesions lichen planus after 7 wks appeared more like lichen of imiquimod therapy to sclerosis and bx was c/w the penis on 1 pt lichen sclerosis. One pt, 21 yo uncircumcised man with lesions on the penis c/w GW vs lichen planus, no biopsy done, after 7 wks of imiquimod had typical lichen planus lesions that evolved into more reticulated/erosive lesions. Both pts skin conditions resolved with stopping imiquimod and circumcision. Conde J et al, 2010 Case report 55 yo woman who used Adverse event  Self-resolving telogen imiquimod 5% cream to a effluvium possibly section of her anterior scalp related to 9 weeks of for 9 weeks for treatment of a daily imiquimod scalp basal cell carcinoma, then treatment for basal cell developed an area of hair loss carcinoma at the site of treatment and

the vertex 6 weeks after stopping imiquimod. Biopsies demonstrated telogen effluvium, which progressed for three months, and then began to reverse itself and her hair growth was normal 5 months after stopping imiquimod therapy. Dominques E et al, 2012 Case report 44 yo man with h/o lichen Adverse event  Possible reactivation of planus, last outbreak 15 yrs lichen planus with brief ago, with lesions on the lower imiquimod treatment on lip actinic chelitis vs lichen the lip planus, treated with imiquimod 5% cream x 4 applications, then developed worsening of lesions on lip and typical LP on extremities Mosher J, Lio P, 2012 Case report 2 yr old healthy girl treated Adverse event  Possible fevers and with daily imiquimod over dermatitis associated lower abdomen for with daily imiquimod use molluscum, developed in a 2 yr old child dermatitis and fevers by 2 wks of treatment. Treatment continued, therapy for presumed cellulitis was started, but fevers continued and pt had a febrile tonic- clonic seizure about 3 wks into imiquimod therapy. Fevers stopped and dermatitis began to resolve one day after imiquimod therapy was stopped Patel U et al, 2012 Case report 74 yo man with no personal  Possible association of or family history of psoriasis new onset, widespread started imiquimod 5% cream psoriasis away from the

to his scalp daily for actinic site of application of keratosis. Within a few weeks daily imiquimod for he developed widespread, actinic keratosis. typical lesions of psoriasis and nail involvement of psoriasis, confirmed by 2 biopsies. These responded to stopping imiquimod, and topical and UV therapies for psoriasis over several months.

Question: Treatment Modalities: Imiquimod 3.75% – Efficacy

Author/Citation Description of Study Population, Sample Size Outcome Summary Points Baker D et al, 2011 Combined results of 2 534 American women > aged Clearance  Complete clearance at randomized, double-blinded 12 years with genital and anal Recurrence the end of 8 weeks: placebo-controlled trials warts >1 cm2, randomized to Adverse events 14.2% - placebo, 28.3%- placebo, or daily treatment imiquimod 2.5% and with imiquimod 2.5% or 36.6% imiquimod 3.75% 3.75% cream until clearance  Safety related of up to 8 weeks. discontinuation rates were 0.9%-placebo, 1.4%-imiquimod 2.5%, 2.3%-imiquimod 3.75%

Question: Treatment Modalities: Imiquimod 3.75% – Safety, adverse events

Author/Citation Description of Study Population, Sample Size Outcome Summary Points Wu J et al, 2012 Pharmacokinetic study 18 adults with GW applied up Blood levels of imiquimod  Steady state was to 1 packet of imiquimod achieved at day 7. 3.75% cream daily for 3 Adverse events  Low blood levels of weeks. Blood was obtained imiquimod were found. before dose 1, 7, 14, and 21.  16.7% reported adverse events.

 No patients discontinued due to adverse events  1 interrupted Rx due to an ulcer at Rx site

Question: Treatment Modalities: Photodynamic Therapy—Efficacy

Author/Citation Description of Study Population, Sample Size Outcome Summary Points Wang H et al, 2012 Case series 56 Chinese patients with Complete clearance rate at 1–  Complete clearance at 1– cervical and EGW treated 4 sessions 4 sessions was 98.2%, with ALA 10% gel for 4 hrs, HPV DNA clearance rate HPV clearance rate was then 635 nm laser at 100 J Recurrence 83.9% cm2. Treatment repeated at 2 Adverse events  10 cases had complete wk intervals for as long as clearance of cervical lesions remained visible. lesions and HPV DNA clearance after 1 treatment  Recurrence was 3.6% at 6–24 months  AEs were “minimal” Yuan-gang L et al, 2012 Case series 40 Chinese pts with 5-25 Clearance at 1 and 3 months  Clearance at 1 month - perianal warts (24 men, 16 following completion of 3 100% and no recurrence women), all underwent sessions of PDT  At 3 months – 6 cases curettage to remove visible Recurrence relapsed, recurrence of lesions down to the dermis, Adverse events 15% then 2 days after curettage,  Patient satisfaction was had PDT: 10% 5-ALA cream 100% at 1 month and applied under an occlusive 95% at 3 months bandage for 3 hrs, warts all  No adverse events treated for 10 min with 635 nm laser at 177 mW/cm2. PDT repeated at 1 and 3 wks. Chen M et al, 2011 Case series 48 HIV negative Chinese Clearance after 1, 2 and 3  62.5% cleared after 1 women with cervical warts, PDT sessions PDT session aged 20–34 years, 9 pts had Recurrence  An additional 25% been treated before with Adverse events cleared after 2 PDT

electrofulgration and has sessions recurrences, 39 were primary  An additional 8.3% presentations. All had 20% 5 cleared after 3 PDT ALA gel on a gauze pad sessions applied to the lesions on the  Complete clearance at 1 cervix and a 5mm border of weeks after 3 PDT normal cervix, for 3 hours. sessions was 95.8% Then all Rxd with 635 nm  No difference in 100J/cm2 at 100mW. PDT clearance rates between was repeated at week 1 and 2 primary presentations if lesions were still present at and pts who had been that evaluation. treated with electrofulgration before  Recurrence rate at 12 months after completion of therapy was 4.4%.  Pts who had total lesion size of <1cm required statistically significantly fewer sessions than those who had lesions >1 cm.  No cervical scarring was observed in any pts  Erythema and edema of the cervix 1 week after a treatment session was observed in 25% of pts  Mild burning or irritation during treatment was reported by 12.5%  5 pts reported menstrual disorders that resolved 2–3 months following the last treatment. Giomi B et al, 2011 Case series 15 Italian adult pts (10 men, 5 Clearance  60% (9/15) pts had women) with external GW. Changes in complete clearance after All GW had previously been immunohistochemical profile 5 treatments

treated topically, but a wash- of cells on biopsy  CD4+ lymphocytes and out period of at least 3 Langerhans cells months took place before the increased in the study. All were treated with superficial dermis over 16.6 % gel ALA under the course of treatment occlusion for 3 hrs, then with  Mild burning, transient 635nm laser at 110 J/cm2 for erythema and erosions 2 min. Evaluated at 48 hrs were noted (no after treatment; at that time, information about how biopsies were also taken. many pts experienced Treatment was repeated every these) 10 days while lesions were still visible, up to 5 treatments. Gattai R et al, 2010 Randomized trial of PDT 22 Italian pts with endoanal Clearance  91% (10/11) pts alone vs PDT followed by warts randomized, 21 Recurrence at 12 months completely cleared with laser CO2 vaporization for completed study. All pts had Pain medication requirements PDT alone (required a endoanal warts ALA 16% gel applied to their mean of 1.36 treatments) lesions using anoscopy, after  90% (9/10) pts 3 hrs, irradiated with 635nm completely cleared with laser for total dose of PDT and CO2 laser 200J/cm2. 10 pts then were (required a mean of 1 treated with laser CO2 treatment) vaporization 60 min after  0/10 pts in PDT group PDT. If lesions did not had a recurrence at 12 resolve, PDT only pts had months repeat PDT treatment at week  2/10 pts in the PDT and 2, 4, and 6. CO2 group had a recurrence at 12 months  1/11 pts in PDT group required post-op paracetamol  7/10 pts in the PDT and CO2 group required post-op paracetamol Nucci V et al, 2010 Case series 15 Italian pts aged 16–38 Clearance  9 pts had complete years (7 men, 7 women) with Recurrence clearance after 1 session

anogenital warts, some on the Adverse events  4 additional pts had urethral mucosa, some treated complete clearance after previously, were all treated 2 sessions with 16% 5 ALA gel under  These 13 pts had no occlusion for 3 hrs, then recurrences in 12 months 630nm laser at 120 mJ/cm2  Minor burning during the for a total dose of 150 J/cm2. procedure was the only Additional treatments were adverse event reported performed every 15 days if needed. Chen M et al, 2010 Case report 9 year old Chinese girl with Clearance  Lesions were completely vulvar warts, treated with Recurrence cleared one week after 20% ALA for 3 hrs, followed Adverse events therapy by 630nm wavelength He-Ne  No recurrence or scarring laser. Treatment was repeated 6 months after 2 in one week. treatments  Slight vulvar pain and edema for one day following therapy Inada N et al, 2011 Case series 40 Brazilian women aged 16–  90% of pts cleared 65 years with various grades completely after 3 of EGW were treated with sessions 20% ALA for 6 hrs, followed  Pts reported burning or by 640nm laser for a total stinging pain during the dose of 200 J/cm2. procedure Sun et al, 2012 Case series 86 adult Chinese pts with Response 1 week after 3  88.4% pts cleared after 3 urethral condyloma (1-40mm treatments were completed treatments from the urethral meatus) and 1 week after 6 treatments  All pts cleared after 6 Rxd with 19.09% ALA for were completed treatments 3hrs, followed by Rx with Recurrence 3 months after all  3 months after treatment 635nm laser with a fluence of treatments were completed completion, 16.3% of pts 100J/cm2 for 20 min. Adverse events (all men) had a relapse Treatment repeated weekly  57% of pts reported an for 3 wks. adverse event, all were transient and tolerable

Question: Treatment Modalities: Podophyllin/podophyllum resin – Efficacy

Author/Citation Study Design Population, Sample Size Outcome Summary Points Lassus A, 1984 Randomized, open-label trial 100 men with penile GW Complete cure after 1 Podophyllotoxin group: of podophyllotoxin 0.5% were randomized to 0.5% treatment and 4 treatments  Cure after 1 treatment 45 solution vs podophyllin 20% podophyllotoxin solution Recurrence at 3 months post (94%) applied at home, 2x/day for 3 starting treatment  Cure after 4 treatments consecutive days per week, 48 (100%) (48pts) or podophyllin 20%  Relapse 11 (23%) ethanolic solution was Podophyllin group: applied once per week in the  Cure after 1 treatment 15 clinic (52 pts). Patients were (29%) evaluated once per week, and  Cure after 4 treatments if they cleared treatment was 37 (71%) stopped. Pts were treated for  Relapse 14 (38%) up to 4 weeks. No statistical tests were performed to evaluate the differences between these cure rates.

“Local adverse reactions were fewer and milder in the podophyllotoxin group” Edwards A, et al, 1988 Randomized, open-label trial 65 men with penile EGW Complete cure Podophyllotoxin group: of podophyllotoxin 0.5% vs were randomized to  Lost to f/u 10 pt podophyllin 20% podophyllotoxin 0.5% 2x/day Relapse 3 months after  Cure after 6 weeks 28/32 for 3 consecutive days each treatment started (88%) week or podophyllin 20%  Relapse 5 (18%) applied by a doctor in a clinic Side effects  Side effects “mild, once per week. Patients were transient” 21/32 (65%) pt evaluated once per week, and CBC, liver function tests, Podophyllin group: treatment was stopped if they chemistry panels were taken  Lost to f/u 4 pts cleared. Treatment was at baseline, resolution, or 3  Cure after 6 weeks 12/19 continued for a maximum of and 6 weeks if no resolution (63%) 6 weeks.  Relapse 4 (33%)

 Side effects “mild, transient” 15/19 (77%) pt

No biochemical abnormalities observed in pts at any time Kinghorn GR et al, 1993 Randomized, open-label trial 205 adult pts were Complete cure at 1 week and Podophyllotoxin group: of podophyllotoxin 0.5% randomized to treatment with at 5 weeks  Cure after 5 weeks 86% lotion vs podophyllin 25% either self-applied Cure of particular wart sites of men, 72% of women solution podophyllotoxin 0.5% lotion at 5 weeks  81% of 180 treated warts 2x/day on 3 consecutive days Podophyllin group: of the week, or physician-  Cure after 5weeks 78% applied podophyllin 25% of men and 62% of solution 2x/week. Pts were women evaluated once per week and  61% of 95 treated sites treatment was stopped if they were clear. Treatment was Comparison of cure rates at 5 continued for up to 5 weeks weeks P = 0.08 in men, 0.14 in women

Comparison of treated sites P < 0.01)

Side effects mild in both groups Lacey CJN, 2003 Open label randomised 358 immunocompetant men Treatment arm—no  Podophyllotoxin 2.5 to controlled trial and economic and women with genital difference in baseline 3x more likely to evaluation of warts. characteristics produce a cure compared podophyllotoxin sol 0.5%, to podophyllin podophyllotoxin cream Podophyllotoxin sol and  Podophyllin: 17% side 0.15% and podophyllin podophyllotoxin cream with effects (not significantly increased odds for remission different from (podophyllotoxin was self- compared to podophyllin (3.0 podophyllotoxin) applied twice a day for 3 and 2.5 times more likely to  No systemic side effects consecutive days + 4 days off produce cure). P Sol from podophyllin. therapy, and 25% statistically sign c/w  Also covered cost podophyllin in tincture of podophyllin but not with p cr effectiveness, and benzoin was applied 2x a in all analysis podophyllotoxin was

week in clinic) All tx for 4 more cost-effective than weeks Side effects were 33% for p podophyllin. sol, 24% for cream and 17% for podophyllin. Ulceration 10-18%, no statistically sign difference in tx side effects

Question: Treatment Modalities: Podophyllin/podophyllum resin – Safety

Author/Citation Study Design Population, Sample Size Outcome Summary Points Ward JW et al, 1954 Case report 18 yo woman, 17 wks 30 hours after the procedure The authors conclude that in pregnant, large (8cm x 7cm) the patient became lethargic, order to prevent systemic condyloma over her then unresponsive and was toxicity: perineum, including vulva diagnosed with toxic  Podophyllin should be and perianal area. Treated encephalopathy. She rapidly applied only to intact with “light sedation,” had developed adynamic ileus and skin “multiple biopsies” of the renal failure and died on the  Podophyllin should be lesion taken, and then the 7th day after the procedure. washed off within 1 hour lesion was covered with Autopsy revealed “congestion “light” 25% podophyllin. The of all organs.” area was not washed off until the pt developed neurologic findings, 30 hours after the procedure. Shirren et al, 1966 Case report 25 yo man with perianal Developed vomiting,  Written in German, no warts, treated with agitation, coma, recovery abstract, information is podophyllin solution took 3 weeks from other reviews Chamberlain MJ et al, 1972 Case report 18 yo previously health She had peripheral motor and  The authors conclude woman in 34th week of her sensory neuropathies as she that the fetal loss and first, healthy pregnancy had awoke from anesthesia, and neuropathy was due to vaginal bleeding and on exam arousal from anesthesia took podophyllum toxicity. was found to have “florid longer than usual. Two days  The authors do not vulvar warts” which were post-operatively, she include information on “friable.” She was put under developed abdominal pain, how long the general anesthesia and treated uterine firmness, and the fetal podophyllum was left on

with 25% podophyllum, a heart rate could no longer be the skin total volume of 7.5ml. heard. She then developed  In this case, the nausea, vomiting, progressive podophyllum was neuropathy including applied to skin described diploplia. 12 days post-op the as “friable” and possibly baby was stillborn, with no over a large area. abnormalities except placental infarcts. The patient’s neuropathy slowly improved, but she was not walking on her own until 3 months post-op. Many months later, the patient did fully recover and went on to conceive again and deliver a healthy baby. Montaldi DH et al, 1974 Case report 20 yo woman with massive Although she initially awoke  Authors concluded this vulvar condylomata was from surgery, she developed was due to podophyllin treated with partial excision, obtundation within 20 hours toxicity. followed by immediate of the surgery. Vomiting, application of podophyllin coma, flaccid paralysis, resin in the operating room. pancreatitis, recovered in 25 days Slater GE et al, 1978 Case report 16 yo girl treated as an 7 hours after being treated in  Authors conclude this outpatient for “massive, clinic she returned to clinic patients toxic friable” vulval condyloma. with abdominal pain, nausea, encephalopathy and She was instructed to wash vomiting, diarrhea and was permanent peripheral the treated area off in 3-4 noted to be lethargic. She was neuropathy was due to hours. treated for dyspepsia and sent podophyllin toxicity. home. The following morning  Podophyllin was used she was unarousable, over a large, friable area admitted to the hospital with and was not washed off fever, tachycardia, decreased in the recommended reflexes, and it was time. discovered that the  Podophyllin toxicity was podophyllin had not been not recognized initially. completely washed off.

The patient had a complicated hospital course with EEG abnormalities, intubation and ventilator support, detoxification therapy with gastric charcoal lavage and venovenous shunt placement, but ultimately recovered and was discharged on day 8. She had long term peripheral neuropathies that did not resolve. Stoehr et al, 1978 Case report 15 yo girl with “large” vulvar The length of time the  Authors conclude this condyloma was treated as an podophyllin was on the skin was due to podophyllin inpatient with 20% is not reported, but the patient toxicity podophyllin. The lesion had developed dizziness, nausea,  Podophyllin was applied been biopsied at some point vomiting, and abdominal pain to a large, friable area during the week prior to the “a short time” after the  Toxicity seemed to treatment. podophyllin was applied. develop very acutely Despite that, the patient was (unclear how long the treated with podophyllin podophyllin was left on) twice during the following and was not recognized, day. She then developed so pt was treated 2 more fever, obtundation, elevated times in one day. liver enzymes, ileus, and over the next several days developed bone marrow failure with clinically significant decreases in all cell lineages. With supportive therapy she recovered fully over 3 weeks. Karol MD et al, 1980 Case report 24 yo woman received in- The baby was born without  The authors conclude clinic topical application of complications, full-term with that the congenital podophyllum resin for EGW, a simian crease on the left abnormalities were due once a week for 5 weeks, palm, bilateral preauricular to podophyllum systemic from the 25th to 29th week of skin tags, and a cardiac absorption.

pregnancy. Each time the murmur that resolved.  There is no information podophyllum was left on for about how extensive an 4 hours, and then washed off. area was treated with During pregnancy, the podophyllum. patient’s only other medications were chloroquine and primaquine due to exposure to malaria. Filley CM et al, 1982 Case report 22 yo woman with vulvar, On the same day as treatment,  Authors conclude this cervical and vaginal she developed lethargy, and was due to podophyllin condyloma applied in the by day 3 after treatment she toxicity office. Pt had had 2 previous developed psychosis, then  Unclear how large the treatments, and podophyllin toxic encephalopathy, ileus, treated area was, or if the was washed off in 1 hour and pancytopenia and peripheral lesions were friable, also she tolerated those neuropathy. She slowly unclear how long treatments. On the 3rd recovered with supportive podophyllin was in treatment, it is unclear if she care, but 10 months after the contact with skin. washed off the podophyllin or treatment still had peripheral not. neuropathy. Conard et al, 1990 Case report 17 yo previously healthy Two hours after the  The authors conclude woman with multiple vaginal procedure the patient had that in this case, and cervical condyloma, and normal motor and sensory podophyllin toxicity was particularly large lesion (3cm function of her lower likely not recognized x 6cm), treated with epidural extremities and was awake immediately due to the anesthesia, followed by CO2 and alert. Thirteen hours post- patient having received laser fulgration to the vulva. op the pt developed fever, epidural morphine and Then immediately following tachypnea, tachycardia, and her neurologic symptoms the laser treatment the patient 16 hours post-op the patient initially being thought to was treated with 17.5% became obtunded. She be due to morphine podophyllin to the “remaining developed worsening fever, overdose or sepsis. condylomata” non-cardiogenic pulmonary  In this case, podophyllin edema, and abnormalities of was possibly used on red blood cells that were broken skin, and was not consistent with a toxic event. washed off in the Blood cultures and lumbar recommended amount of puncture were normal. She time eventually developed renal

failure, coma, and died 26 hours post-op. The podophyllin was washed off sometime between 16 and 26 hours post-operatively.

Question: Treatment Modalities: Podophyllin (podophyllum) – Reviews

Author/Citation Study Design Population, Sample Size Outcome Summary Points Lacey CJN et al, 2012 European Guidelines for Recommended therapies:  Recommend against the management of patient applied: podophyllotoxin, using podophyllin, cite anogenital warts – based on imiquimod, sinecatechins that 10% contains a systemic review of provider administered: cryotherapy, TCA, mutagenic compounds randomized controlled electrocautery, scissor excision quercetin and trials kaempherol, and severe systemic toxicity after topical use has been described. Gormley RH and Kovarik CME article outlining  Recommended against CL, 2012 approach to genital wart using podophyllin, treatment in the (level IIB evidence) immunocompromised host, citing low efficacy aimed at dermatologists compared to other therapies, possibility of serious side effects Fraser PA et al, 1993 Review article with one set Authors arguing AGAINST the use of  The arguments that of authors arguing for a podophyllin argued: podophyllin is less motion to eliminate - Podophyllin formulations are unstable, standardized, possibly podophyllin as a treatment not standardized, while podophyllotoxin is less effective, for EGW used in Dublin’s standardized potentially more venereal disease clinics, - Systemic toxicity resulting in death, fetal dangerous, and more and another author arguing loss, and neurotoxicity has been reported expensive than to continue use of from use (usually mis-use) of podophyllin, podophyllotoxin were podophyllin. and not with podophyllotoxin not countered, and were - Podophyllotoxin has clearance rates and even specifically recurrence rates that are at least the same conceded in the paper. as podophyllin, and in many studies better

than podophyllin  However, the motion to -Podophyllotoxin therapy is less expensive eliminate podophyllin than in-office podophyllin therapy from the treatment guidelines was sturck Author arguing FOR the use of down, with a vote of podophyllin argued: 129 voting for, and 136 -When podophyllin is used correctly in the voting against. office there are low risks of systemic toxicity -Home therapy of any type is often unsuccessful because patients are bad at identifying new or small lesions -The Dublin Venereal Disease society wants people to come into clinic for treatment both because it is economically good for the clinic, and because it confers more opportunities for counseling and screening

Petersen CS, Weismann Using high-pressure liquid Basic science study, used  Quercetin and K, 1995 chromatography, the 3 batches of podophyllin kaempherol made up amounts of 2 mutagenic 20% 2.5-3.8 and 6.0-6.4% of flavonoids, quercetin and the dry substance of kaempherol found in podophyllin 20%, and podophyllin 20% resin podophyllotoxin made were estimated. up 12.7-13.8% of the dry substance of podophyllin. Podophyllotoxin clearly safe, case reports  Summary of data about Longstaff E, 2001 Review of the literature on Review of the studies of 2 deaths with topical application of podophyllin: podophyllin safety-opinion including animal studies, podophyllin (these were related to open information on lack of and data case reports, reproductive wounds allowing entry of the drug stability of product, toxicity for podophyllin systemically, and large areas that were questionable safety with and podophyllotoxin treated). Teratogenicity and reproductive regard to teratogenicity safety studies are limited, some data on lack of studies, some cases of stability of the drug podophyllin systemic toxicity with topical application, low

efficacy Von Krogh G, 2001 Review of safety of Same as above Issues covered included: long term efficacy  Similar issues covered podophyllin office rates not confirmed, severe local and therapy—opinion and data systemic toxicity, mutagenic properties, and quality control problems.

Question: Treatment Modalities: Other treatments – Efficacy

Author/Citation Description of Study Population, Sample Size Outcome Summary Points Jardine et al, 2012 Randomized controlled trial Healthy adults with GW Primary endpoint – recurrent  Patients were analyzed of HPV6 L1 presenting to STD clinics in GW 2 months after by site Australia (144) and China destructive treatment  2 higher doses of HPV6 (236), L1 were associated with Pts had GW treated with less disease recurrence at destructive modalities, then 6 months (no statistical were randomized to receive test for significant placebo or 1ug, 5ug, or 25 ug performed) at the of HPV6 L1, 2 doses, 4 Australia site, no weeks apart. differences seen at the China sites.  No serious adverse events were reported in any group. Friedman M et al 2009 Case series of new 74 adult Israeli pts (48  Complete clearing was immunomodulators tellurate women 26 men) with EGW seen in 76% of pts AS101 treated with the topical  At 6 months after immunomodulator tellurate treatment, 4% of pts had AS101, 15%. All pts applied recurrence the cream 2x/day for up to 16  Most common adverse weeks events were itching, soreness, and erythema Sethuraman G et al, 2009 Case series of Rx with PDL 5 children with perianal and Complete clearance  5/5 had complete perianal warts (reported as clearance after an

part of a case series of 61 average of 2.2 children with all types of treatments, avg of 7.1 warts) were treated with J/cm2 with avg 56 pulses pulsed-dye laser (PDL). per treatment  No comments on how these particular pts tolerated therapy

Question: Treatment Modalities: Special Populations: Pregnant Women

Author/Citation Description of Study Population, Sample Size Outcome Summary Points Yang et al, 2012 Case series 5 pregnant (2 or 3 trimester) Clearance, recurrence, AE,  All women had Chinese women aged 25–32 pregnancy outcome completed clearance after years, with vulvar, perianal up to 4 Rx warts each Rx with ALA and  No recurrences with 6– PDT up to 4 treatments, 1-2 25 months of f/u weeks apart.  No serious adverse events  All delivered healthy babies Ciavattini et al, 2012 Case series 4 pregnant Italian women (2 Clearance at 4 weeks of  Outcome at 4 weeks of or 3 trimester) 5% imiquimod therapy, AE, pregnancy therapy: 2 had completed applied once per day, 3/days outcomes clearance, 2 had partial per week x 4 weeks. clearance  3 of 4 women had erythema as an adverse event  3 women delivered by C- section due to non- reassuring FHR at full term  1 woman developed eclampsia and had C- section at 34 weeks

 All infants healthy Eassa B et al, 2011 Case series 40 Egyptian pregnant women, Complete, partial, minimal  Overall improvement aged 20–35 yrs with EGW responses was 85% and was related were treated with weekly Adverse events to reactivity to tuberculin intradermal injections of  47.5% had complete purified protein derivative clearance (PPD)  37.5% had a partial response  7.5% had a minimal response  7.5% had no response  “Minimal” side effects

Question: Treatment Modalities: Special Populations: Immunocompromised

Author/Citation Description of Study Population, Sample Size Outcome Summary Points Trakatelli M et al, 2010 Review of the safety and Review of other studies – Graft rejection  No graft rejection has efficacy of imiquimod 5% describes a total of 14 reports Signs of systemic toxicity been reported to date in a cream in organ transplant (case series and randomized (e.g. clinically increased pt being treated with patients trials) of more than 100 organ serum creatinine in renal Tx imiquimod transplant pts treated with pts)  No clinically significant imiquimod for various skin changes in lab work or diseases (including Ulrich et other signs of systemic al below) toxicity Saiag P et al, 2009 Case series 50 HIV adults in Belgium and Complete clearance at 16 wks  Complete clearance France, on ART with CD4+ LR and HR HPV DNA in observed in 32% of pts at counts ≥200 cells/mm3 and lesions 16 wks plasma viral RNA <104  At enrollment, 90% of copies 4 weeks prior to lesions had HPV DNA, therapy, with EGW. became undetectable Imiquimod 5% cream was after 16 wks of treatment applied to all warts 3x/wk for in 40% of those studied up to 16 wks  No changes in CD4 count or viral load seen during the study

 Erythema (seen in 22%) and ulceration (seen in 12%) were the most common local reactions Ulrich C et al, 2005 Randomized, placebo- 43 pts with kidney, heart, or Laboratory abnormalities  No graft rejection in controlled trial of imiquimod liver Tx applied 2 sachets of Graft failure either arm for actinic keratosis to imiquimod 5% cream or Requirements of increased  No significant changes or establish safety in solid organ vehicle to an area of 100cm2 immunosuppression trends in laboratory transplant pts 3x/wk for 16 wks (regardless analyses of lesions clearing)