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752 Diseases of the Colon & Rectum Volume 57: 6 (2014)
BACKGROUND:  Men who have sex with men have
increased prevalence of...
Diseases of the Colon & Rectum Volume 57: 6 (2014) 753
caused by low-risk (LR) strains of HPV are estimated to
affect 1% o...
SILVERA ET AL: CONDYLOMA AMONG HIV-NEGATIVE MSM754
treated or considered recurrence. Most disease was treated
­in-office w...
Diseases of the Colon & Rectum Volume 57: 6 (2014) 755
Participants with moderate and extensive perianal disease
were ofte...
SILVERA ET AL: CONDYLOMA AMONG HIV-NEGATIVE MSM756
of treatments needed for clearance, nor did patient age or
receiving qH...
Diseases of the Colon  Rectum Volume 57: 6 (2014) 757
disease did not significantly differ and was 48.3 (95% CI,
32.0-64.5...
SILVERA ET AL: CONDYLOMA AMONG HIV-NEGATIVE MSM758
were the shorter duration of follow-up (AOR, 1.3; 95%CI,
1.1-1.5), bein...
Diseases of the Colon  Rectum Volume 57: 6 (2014) 759
than 1 treatment for clearance, but had no effect on re-
currence af...
SILVERA ET AL: CONDYLOMA AMONG HIV-NEGATIVE MSM760
ate how changes in those habits may affect treatment or
recurrence.
The...
Diseases of the Colon  Rectum Volume 57: 6 (2014) 761
	27.	 Carrasco D, vander Straten M, Tyring SK. Treatment of ano-
gen...
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Manejo del condiloma acuminado anal

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Manejo del condiloma acuminado anal

  1. 1. 752 Diseases of the Colon & Rectum Volume 57: 6 (2014) BACKGROUND:  Men who have sex with men have increased prevalence of both human papillomavirus and anogenital condyloma. OBJECTIVE:  Risk factors for multiple treatment and recurrence of anal condyloma were examined. DESIGN:  This is a retrospective study of HIV-negative men who have sex with men who were treated for anal condyloma. SETTINGS:  This study was conducted in a private surgical practice. PATIENTS:  The patients were HIV-negative men who have sex with men, aged 18 years or older. INTERVENTION(S):  Ablation with electrocautery or CO2 laser was performed, as well as excision and topical imiquimod condyloma treatment adjuvant. MAIN OUTCOME MEASURES:  Primary clearance, defined as 4 months of condyloma-free survival posttreatment, and recurrence, defined as any anal condyloma diagnosis after primary clearance. RESULTS:  Of 231 participants, 207 achieved primary clearance (median age, 32.0 years) and were followed (median, 18.2 months) after primary treatment. Most had intra-anal and perianal condyloma (56%), were treated with electrocautery ablation (79.2%), and required 1 treatment (range, 1–6) for clearance. There were 57 recurrences (median, 12 months). One-third each had minimal, moderate, or extensive disease. Forty-six percent of patients received imiquimod posttreatment adjuvant. High-grade dysplasia was found in 31% at presentation and 43% during follow-up. Factors associated with requiring multiple treatments for clearance were participants having moderate disease (adjusted odds ratio, 6.0 (1.7–21.4)) and receiving imiquimod adjuvant (adjusted odds ratio, 4.7 (2.0–10.6)). No single factor predicted recurrence, but those with moderate disease experienced recurrences significantly sooner (median, 25 months of follow-up). LIMITATIONS:  This was a retrospective chart review, it was limited to a single practice, and it excluded those who did not achieve primary clearance. CONCLUSIONS:  Most men who have sex with men have intra-anal and perianal condyloma and concomitant high-grade dysplasia is common. Most achieved clearance with 1 treatment. Having both intra-anal and perianal condyloma, increased severity of disease, and imiquimod adjuvant were significant predictors of requiring multiple treatments for clearance. No identified risk factors proved a significant predictor of recurrence. KEY WORDS:  Condyloma; Men who have sex with men; Anal; Human papillomavirus; Imiquimod; Human papillomavirus vaccine. H uman papillomavirus (HPV) is the most com- mon sexually transmitted infection in the United States. An estimated 79 million Americans are currently infected with HPV, and approximately 14 mil- lion new infections occur each year.Anogenital condyloma Anal Condyloma Treatment and Recurrence in ­HIV-negative Men Who Have Sex With Men Richard J. Silvera, M.P.H.1 • Casey K. Smith, J.D.1 • Kristin A. Swedish, M.D., M.P.H. 2 Stephen E. Goldstone, M.D.3 1 Department of Medical Education, Icahn School of Medicine at Mount Sinai, New York, New York 2 Department of Medicine, Montefiore Medical Center, New York, New York 3 Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, New York Dis Colon Rectum 2014; 57: 752–761 DOI: 10.1097/DCR.0000000000000080 © The ASCRS 2014 Funding/Support: Mr Silvera’s participation was funded by the Icahn School of Medicine at Mount Sinai Summer Scholars Program. Dr Smith’s participation was funded by a grant through a Clinical and Translational Science Award from the NIH to the Icahn School of Medi- cine at Mount Sinai. No other funding was received. Financial Disclosure: None reported. Presented at the meeting of the International Papillomavirus Confer- ence, San Juan, Puerto Rico, November 30 to December 6, 2012. Correspondence: Stephen E. Goldstone, M.D., 420 West 23rd St, New York, NY 10011. E-mail: Goldstone.stephen@gmail.com ORIGINAL CONTRIBUTION
  2. 2. Diseases of the Colon & Rectum Volume 57: 6 (2014) 753 caused by low-risk (LR) strains of HPV are estimated to affect 1% of sexually active adults in the United States with approximately 250,000 new cases diagnosed each year.1 A study of the National Health and Nutrition Examination Survey (NHANES) found that 5.6% of 18 to 59 year olds reported ever having been diagnosed with genital condy- loma.2 In addition, initial visits to clinicians in the United States for treatment of genital warts almost doubled from 233,000 in 2001 to 453,000 in 2011. The incidence of ano- genital condyloma in Canada also has been documented to be increasing among men from 125/100,000 in 1985 to 150/100,000 in 2004.3,4 Studies have found that men who have sex with men (MSM) demonstrate a higher prevalence of both high- and low-risk anal HPV infections. A multicity study of 1218 HIV-negative MSM found a 57% prevalence of anal HPV infection that did not vary by age (18-89 years) or geographic location; LR HPV types 6 and 11, which are re- sponsible for 90% of anogenital condyloma, were the sec- ond and third most common strains.5 A large-scale study found that the incidence of external genital lesions was 4.26 per 100 person-years among MSM compared with 1.39 per 100 person-years among heterosexual men.6 An- other cross-sectional study found that HIV-positive MSM had 2.2 increased odds of having anal condyloma than HIV-positive heterosexual men.7 Clinicians use many different methods to treat anal condyloma including ablation with cautery or laser, cryo- therapy, and topical medications (applied either by the patientortheclinician).8–10 However,recurrenceaftertreat- ment is common. A study of 140 men and women treated surgically for extensive perianal and intra-anal condyloma reported a 25% recurrence rate within 12 months.11 An- other study of patients presenting for surgical treatment of extensive perianal and intra-anal condyloma reported a 40% recurrence rate.12 To date, research demonstrated that quadrivalent HPV (qHPV) (Gardasil, Merck & Co, Inc) vaccination re- duced the risk of high-grade squamous intraepithelial le- sion (high-grade dysplasia, HSIL) recurrence after ablation among vaccinated patients in comparison with nonvac- cinated (OR, 0.5), but vaccination has not been shown to have any effect on condyloma recurrence posttreatment.13,14 Given that reports of condyloma treatment efficacy deal largely with heterosexual populations and rarely study intra-anal disease, but in MSM both the incidence of LR HPV anal infection and the burden of anal condyloma are high, we endeavored to determine the effectiveness con- dyloma treatment in a cohort of HIV-negative MSM and identify factors that affect both cure rates and recurrence. MATERIALS AND METHODS This study represents a retrospective analysis of a pro- spectively followed cohort treated for perianal and in- tra-anal condyloma at a private surgical practice (S.G.) between February 2008 and March 2012. To be included in the study, patients had to be new patients to the prac- tice, ­HIV-negative MSM with anorectal condyloma that achieved primary clearance, and have at least 1 follow-up visit at least 4 months after clearance. Primary clearance wasdefinedasatleast4monthswithoutevidenceof 1)peri- anal condyloma on physical examination or 2) ­intra-anal condyloma on either standard or ­high-resolution anos- copy (HRA). Recurrence was defined as subsequent diagnosis of perianal or intra-anal condyloma after achieving primary clearance. The Icahn School of Medicine at Mount Sinai Program for the Protection of Human Subjects approved this study. In addition to course of treatment, medical re- cords were abstracted for clinical presentation; smoking history; history of chlamydia, gonorrhea, syphilis, or her- pes infection; and monogamy at initial presentation. For the purpose of analysis, condyloma were catego- rized based on medical record descriptions and photo- graphic documentation taken during HRA as 1) minimal: scattered, small condyloma with prominent disease-free areas; 2) moderate: widespread condyloma but with ­disease-free areas; or 3) extensive: circumferential or ­near-circumferential condyloma (Fig. 1). Treatment mo- dalities used included excision, electrocautery ablation (ECA), and CO2 laser ablation (laser). Treatment modality was selected based on clinician recommendation and par- ticipant preference. Excision and ECA occurred in-office, whereas laser ablation occurred in the operating room. Participants who received a complete 3-injection course of qHPV vaccination before or during participation in this study were considered vaccinated for this analysis. Participants presenting to the practice for evalua- tion of HPV-related anorectal disease were assessed by digital anorectal examination, anal cytology, and standard anoscopy. If insurance allowed, participants were tested for oncogenic HPV by Hybrid Capture 2 (HC2) (Digene Corporation, Gaithersburg, MD). Those with condyloma and any other abnormality were evaluated with HRA as previously described.15 In brief, during HRA the anal ca- nal is stained with acetic acid, and the squamocolumnar transformation zone and anal canal are examined with magnification.We apply Lugol Iodine to better distinguish low-grade squamous intraepithelial lesion ­(low-grade dysplasia, LSIL) from HSIL. High-grade dysplasia and anal squamous-cell cancer are typified by acetowhite, Lugol-negative epithelium with vascular abnormalities (mosaicism, punctuation, and atypical vessels), abnor- mal glands, friability, ulceration, and mass effect. Lesions suspicious for HSIL are biopsied for histology. We typi- cally biopsy at least 1 wart in patients with condyloma but absent lesions suspicious for HSIL. Condyloma were de- fined based on visual appearance or pathology report. Flat areas of LSIL without verrucous characteristics were not
  3. 3. SILVERA ET AL: CONDYLOMA AMONG HIV-NEGATIVE MSM754 treated or considered recurrence. Most disease was treated ­in-office with HRA-guided ECA or excision of small le- sions. Large-volume disease that required an operating room was treated with HRA-guided laser ablation. Patients with moderate and extensive disease were ex- amined twice at 6-week intervals posttreatment;those with minimal disease were examined at 12 weeks posttreatment. Follow-up included digital anorectal exam and standard anoscopy. Thereafter, all patients were evaluated every 3 months for 1 year and then every 6 months for an addi- tional year. All participants had anal cytology at 6-month intervals; participants with abnormalities were evaluated with HRA, and biopsies were collected as indicated. After 1 year, participants with normal cytology and no obvious recurrence were seen yearly. Those with HSIL or flat LSIL continued in follow-up as previously described.16 Recur- rence was treated most often with HRA-guided ECA, or, if limited and external, with either excision or imiquimod. FIGURE 1.  Condyloma classification. A, Minimal perianal condyloma with a small cluster (arrow). B, Minimal intra-anal condyloma with a single lesion (arrow). C, Moderate perianal condyloma with multiple lesions scattered circumferentially around the verge but with significant disease free areas. D, Moderate intra-anal condyloma with a large cluster lesion and a smaller single lesion (arrows). E, Extensive intra-anal condyloma with almost complete circumferential involvement (arrows).
  4. 4. Diseases of the Colon & Rectum Volume 57: 6 (2014) 755 Participants with moderate and extensive perianal disease were often treated with imiquimod as an adjuvant in the hope of decreasing recurrence beginning approximately 2 weeks postablation (or once significant healing occurred) for a 4-month course. Participants could undergo mul- tiple treatments to clear disease in an effort to achieve the primary end point of 4 months disease-free survival. STATISTICAL METHODS Quantitative variables are reported as median (range). Categorical variables are reported as frequency (%) and total n. Categorical variables were analyzed by using the χ2 and Fisher exact tests and quantitative variables by us- ing the Student t tests. A p value of <0.05 was considered significant. Significant bivariates were entered into multi- variable logistic regression, results of which were reported as adjusted ORs (AORs), 95% CIs, and p values. An AOR that did not include 1 or a p value of <0.05 was consid- ered statistically significant. Finally, Kaplan-Meier curves were prepared examining time from first treatment to re- currence or end of follow-up. Participants were censored either at first confirmed recurrence of anogenital condy- loma or at last recorded follow-up visit. Factors were as- sessed for significance in the Kaplan-Meier curve by using a generalized Wilcoxon method. A p value <0.05 was con- sidered significant. RESULTS We identified 313 HIV-negative MSM ≥18 years of age with intra-anal and perianal condyloma seen between February 2008 and March 2012 (Fig. 2). Eighty MSM were excluded because they did not have adequate follow-up postprimary ablation. An additional 2 were excluded be- cause they were treated solely with imiquimod and not an ablative technique, leaving 231 evaluable for clearance and recurrence. Of these MSM, 207 (89.6%) achieved primary clearance, and their characteristics are detailed in Table 1. Table 2 details characteristics of the 24 patients (10.4%) who did not achieve primary clearance. Participants who cleared had a median age of 32.0 (range, 19.7-73.8) years and were followed for a median of 18.2 (3.2-54.1) months after primary treatment. Be- fore referral to the practice, 126 (60.9%) participants had a previous history of condyloma treatment, most often with either clinician- or patient-applied topical therapies or cryotherapy. The most common presentation was both intra-anal and perianal condyloma found in 117 partici- pants (56%), with an even distribution of minimal, mod- erate, and extensive disease. Electrocautery ablation was the initial therapy in 164 (79.2%) participants, 34 (16.4%) required laser treatment in the operating room, and 9 (4.3%) were treated with excision. Duration of treatment ranged from 0 to 42.3 months with a mean of 2.2 months; median, 0 months. The median number of treatments re- quired for clearance was 1 (range, 1-6). Imiquimod was used as a posttreatment adjuvant in 112 (46.4%) par- ticipants. Quadrivalent HPV vaccine was not used ther- apeutically but was offered to many patients as off-label immunization, and 135 (64.6%) received it at some point either before or during the study. In addition to condy- loma, HSIL was found in 64 (30.9%) participants at initial presentation and in 88 (42.5%) during follow-up. No par- ticipant had anal cancer. One hundred fifty-five participants (74.9%) expe- rienced clearance after a single treatment. The median time to clearance was 0 (range, 0-42.3) months. Partici- pants requiring more than 1 treatment were more likely to have both perianal and intra-anal condyloma (p = 0.001), more extensive initial presentation (p < 0.001), or to have received imiquimod as a posttreatment adjuvant (p < 0.001). Treatment method did not affect the number HIV-negative MSM age > 18 with anogenital condyloma n = 313 Excluded: • Inadequate follow-up: n = 80 • Primary treatment with imiquimod: n = 2 Evaluable for primary end point: n = 231 Achieved primary clearance: n = 207 No primary clearance: n = 24 FIGURE 2.  Study flow chart. MSM = men who have sex with men.
  5. 5. SILVERA ET AL: CONDYLOMA AMONG HIV-NEGATIVE MSM756 of treatments needed for clearance, nor did patient age or receiving qHPV (Table 1). Table 3 presents factors associated with requiring more than 1 treatment for clearance with multivariable analysis. Moderate condyloma at presentation had an AOR of 5.9 (95% CI, 1.7-20.7), extensive condyloma had an AOR of 1.3 (95% CI, 0.62-2.8), as well as receiving imiquimod as an ad- juvant with anAOR of 4.1 (95% CI,1.8-9.0).Moderate con- dyloma severity and imiquimod adjuvant were significantly associated with each other (p = 0.03) and, therefore, may be confounders rather than independent variables associated with requiring multiple treatments for clearance. Recurrence postclearance occurred in 57 partici- pants after a median time from their first treatment of 11.7 (range, 5.9-48.3) months. Kaplan-Meier curves of time to recurrence from first treatment for those with minimal, moderate, and extensive disease are shown in Figure 3. Probability of recurrence at 1 year was 9.9% (95% CI, 0-22.4) for those with minimal disease, 19.5% (95% CI, 2.5-36.4) for those with moderate disease, and 15.3% (95% CI, 0-40.8) for those with extensive disease. The probability of recurrence increased to 14.1% (95% CI, 3.8-24.4), 29.9% (95% CI, 18.2-41.6), and 20.3% (95% CI, 0.3-40.3) at 2 years and to 15.5% (95% CI, 6.3- 24.7), 32.5% (95% CI, 21.2-43.8), and 28.1% (95% CI, 14.3-43.4%) at 3 years for those with minimal, moderate, and extensive disease. The estimated median time to re- currence from first treatment for minimal and extensive TABLE 1.  Traits associated with recurrence and multiple treatment events for primary clearance Total (n = 207) Recurrence (n = 57) No recurrence (n = 150) p 1 Treatment for clearance (n = 155) >1 Treatment for clearance (n = 52) p Age, y, median (range) 32.0 (19.7–73.8) 32.4 (20.2–73.8) 31.9 (19.7–71.4) NS 33.0 (19.7–73.8) 30.9 (20.2–56.9) NS Duration of follow-up, mo, median (range) 18.2 (3.2–54.1) 24.0 (6.2–54.1) 16.6 (3.2–49.8) 0.003 17.0 (3.2–50.8) 21.9 (6.6–54.1) 0.020 Time to primary clearance, mo, median (range) 0 (0–42.3) 0 (0–37.6) 0 (0–42.3) NS 0 (0–6.7) 4.9 (1.2–42.3) <0.001 History of smoking  Yes 16.4% (34) 14.0% (8) 17.3% (26) NS 18.1% (28) 11.5% (6) NS  No 83.6% (173) 86.0% (49) 82.7% (124) 81.9% (127) 88.5% (46) Monogamous at visit 1  Yes 30.9% (64) 31.6% (18) 30.7% (46) NS 30.3% (47) 32.7% (17) NS  No 69.1% (143) 68.4% (39) 69.3% (104) 69.7% (108) 67.3% (35) Location of presenting condyloma  Perianal 9.7% (20) 5.3% (3) 11.3% (17) NS 9.7% (15) 9.6% (5) 0.001 Intra-anal 34.3% (71) 31.6% (18) 35.3% (53) 41.3% (64) 13.5 (7)  Both 56.0% (116) 63.2% (36) 53.3% (80) 49.0% (76) 76.9% (40) Severity of condyloma  Minimal 34.3% (71) 22.8% (13) 38.7% (58) NS 41.9% (65) 11.5% (6) 0.001 Moderate 37.2% (77) 43.9% (25) 34.7% (52) 34.2% (53) 46.2% (24)  Extensive 28.5% (59) 33.3% (19) 26.7% (40) 23.9% (37) 42.3% (22) Initial condyloma treatment  Excision 4.3% (9) 1.8% (1) 5.3% (8) NS 5.2% (8) 1.9% (1) NS Electrocautery 79.2% (164) 84.2% (48) 77.3% (116) 79.4% (123) 78.8% (41)  CO2 laser 16.4% (34) 14.0% (8) 17.3% (26) 15.5% (24) 19.2% (10) Total treatment events for clearance, median (range) 1.0 (1–6) 1.0 (1–6) 1.0 (1–6) NS 1.0 (1–1) 2.0 (2–6) N/A History of STI (gonorrhea, chlamydia, or syphilis)  Yes 27.5% (57) 26.3% (15) 28.0% (42) NS 28.4% (44) 25.0% (13) NS  No 72.5% (150) 73.7% (42) 72.0% (108) 71.6% (111) 75.0% (39) Any oncogenic HPV  Yes 58.0% (120) 59.6% (34) 57.3% (86) NSa 62.6% (97) 44.2% (23) NSa  No 24.6% (51) 26.3% (15) 24.0% (36) 24.4% (38) 25.0% (13)  Not tested 17.4% (36) 14.0% (8) 18.7% (28) 12.9% (20) 30.8% (16) Quadrivalent HPV vaccination  Yes 64.3% (133) 68.4% (39) 62.7% (94) NS 61.3% (95) 73.1% (38) NS  No 35.7% (74) 31.6% (18) 37.3% (56) 38.7% (60) 26.9% (14) Imiquimod adjuvant used in treatment  Yes 46.4% (96) 52.6% (30) 44.0% (66) NS 36.1% (56) 76.9% (40) 0.001  No 53.6% (111) 47.4% (27) 56.0% (84) 63.9% (99) 23.1% (12) STI = sexually transmitted infection; HPV = human papillomavirus. a Excluding participants“not tested.”
  6. 6. Diseases of the Colon Rectum Volume 57: 6 (2014) 757 disease did not significantly differ and was 48.3 (95% CI, 32.0-64.5) months but 24.0 (95% CI, 19.6-28.5) months for those with moderate disease. Neither age, smoking history, monogamy, location or severity of condyloma, requiring more than 1 treatment for primary clearance, total number of treatments, history of oncogenic HPV, treatment modality, sexually transmit- ted infection history, receiving qHPV, or imiquimod adju- vant proved a significant predictor of recurrence. Survival analysis considered all recorded variables,including smok- ing history, monogamy, high-risk HPV infection, location of presenting condyloma, history of sexually transmitted infection, receiving qHPV, and severity of presenting con- dyloma. Only severity of presenting condyloma was sig- nificantly associated with time to recurrence (p = 0.001; other data not shown). The 24 MSM that did not achieve primary clearance differed significantly from those that did with respect to the fact that they had a shorter duration of follow-up (me- dian, 6.1 (range, 4.1-18.6) months [p 0.001]), were less likely to have only intra-anal condyloma (4.2%, p = 0.008), less likely to receive qHPV (29.2%, p = 0.001), but more likely to receive imiquimod as a postablation adjuvant (70.8%, p = 0.03; Table 2). Factors associated with failing to achieve primary clearance with multivariable analysis TABLE 2.  Traits associated with failure to achieve primary clearance Characteristic Total (n = 24) Bivariate p Multivariate analysis AOR p Age, y, median (range) 29.6 (20.7–57.8) NS Duration of follow-up, mo, median (range) 6.1 (4.1–18.6) 0.001 1.3 (1.1–1.5) 0.001 History of smoking  Yes 25.0% (6) NS  No 75.0% (18) Monogamous at visit 1  Yes 29.2% (7) NS  No 70.8% (17) Location of presenting condyloma  Perianal 20.8% (5) 0.008 1 -  Intra-anal 4.2% (1) 29.7 (2.6–341.9) 0.007  Both 75.0% (18) 2.9 (0.63–12.9) 0.172 Severity of condyloma  Minimal 37.5% (9) NS Moderate 45.8% (11)  Extensive 16.7% (4) Initial condyloma treatment  Excision 8.3% (2) NS Electrocautery 75.0% (18)  CO2 laser 16.7% (4) Total treatment events, median (range) 2.0 (1.0–5.0) NS History of STI (gonorrhea, chlamydia, or syphilis)  Yes 45.8% (11) NS  No 54.2% (13) Any oncogenic HPV  Yes 58.3% (14) NS No 12.5% (3)  Not tested 29.2% (7) Quadrivalent HPV vaccination  Yes 29.2% (7) 0.001 5.8 (1.8–18.0) 0.003  No 70.8% (17) 1 - Imiquimod adjuvant used in treatment  Yes 70.8% (17) 0.03 0.27 (0.07–1.0) 0.051  No 29.2% (7) 1 - AOR = adjusted odds ratio; STI = sexually transmitted infection; HPV = human papillomavirus. TABLE 3.  Multivariable logistic regression for 1 treatment for clearance vs 1 treatment for clearance AOR (95% CI) p Location of presenting condyloma  Perianal 1 -  Intra-anal .4 (0.01–1.7) 0.209  Both perianal and intra-anal 1.0 (0.33–3.1) 0.976 Severity of presenting condyloma  Minimal 1 -  Moderate 6.0 (1.7–21.4) 0.006  Extensive 1.4 (0.66–3.1) 0.365 Imiquimod adjuvant  Yes 4.7 (2.0–10.6) 0.001  No 1 - AOR = adjusted odds ratio.
  7. 7. SILVERA ET AL: CONDYLOMA AMONG HIV-NEGATIVE MSM758 were the shorter duration of follow-up (AOR, 1.3; 95%CI, 1.1-1.5), being less likely to just have intra-anal condyloma (AOR, 29.7; 95% CI, 2.6-341.9), and not receiving qHPV (AOR, 5.8; 95% CI, 1.8-18.0). The 80 participants that were excluded because of inadequate follow-up did not significantly differ from included patients with respect to age, monogamy, smok- ing status, history of oncogenic HPV, treatment modal- ity, sexually transmitted infection history, or receiving qHPV (data not shown). They were, however, significantly less likely to have both intra-anal and perianal disease (p = 0.001). DISCUSSION This study shows that requiring multiple treatment events to achieve primary clearance of anogenital condyloma is associated with increased severity of disease and the use of an imiquimod as posttreatment adjuvant. Although no factors were significantly associated with posttreatment condyloma recurrence, participants with moderate sever- ity of disease developed recurrence in a significantly short- er time from the first treatment than those with minimal or extensive disease. Many strategies have been used to address the rising rates of HPV infection and condyloma, but it remains a concern, particularly for MSM. Quadrivalent HPV ­vaccine has been shown to decrease anogenital condyloma in MSM, but male vaccination rates remain low.6,14 Since 2011, when qHPV vaccination guidelines were expanded to include males, only an estimated 8.3% of males aged 13 to 17 years were vaccinated.17 It follows that anogeni- tal condyloma will remain a significant health burden for MSM until vaccination rates increase among this popu- lation. Our data illustrate the crucial point that condy- loma in MSM most often involve both the perianal and ­intra-anal areas. Therefore, clinicians treating MSM with visible external condyloma must be sure to rule out ­intra-anal disease. Large-scale studies are still needed to determine the effect of qHPV vaccination on condyloma recurrence. Another barrier to successful treatment of ­intra-anal condyloma is that there are no Food and Drug ­Administration-approved patient-applied topical thera- pies available. These barriers suggest that new treatments or prevention strategies are needed to address condyloma among MSM. In our hands, ECA was the preferred treat- ment modality for perianal and intra-anal condyloma for several reasons. The vast majority of patients achieved clearance with a single ECA treatment. Moreover, ECA allows full-thickness destruction of condyloma in a sin- gle treatment. Conversely, treatment with imiquimod or cryotherapy often requires multiple treatments over pro- longed periods.10 Cryotherapy and topical agents produce variable depths of necrosis, necessitating repeated treat- ments separated by an interval to allow for healing, es- pecially when treating bulky, hyperkeratotic condyloma. Knowing that we had achieved full-thickness destruction allowed us to feel comfortable not seeing participants after ECA for 6 to 12 weeks. Those treated with cryotherapy or topical agents are often seen at 2- to 3-week intervals for possible re-treatment. The primary drawback for ECA is the requirement of local anesthetic, which is not necessary for either cryother- apy or clinician-applied topical agents.18–24 In our view, the greater likelihood of achieving clearance after just 1 treat- ment makes ECA the better approach. Although pain and other morbidities like bleeding might be greater with ECA in comparison with other less extensive treatments, we be- lieve the benefit derived from fewer visits make it the bet- ter approach. Clearly, those who have extensive disease are best treated in the operating room where the goal of either laser or cautery ablation is also to produce full-thickness destruction of the condyloma. Approximately one-fourth of patients required mul- tiple treatments to achieve clearance. As would be expect- ed, those with the most extensive disease were statistically more likely to require multiple treatments to clear.Surpris- ingly, having both intra-anal and perianal condyloma did not significantly affect the need for multiple treatments in multivariable analysis. Imiquimod as a posttreatment adjuvant was significantly associated with requiring more 1.0 Cumulative survival Condyloma serverity Minimal Moderate Extensive 0.8 0.6 0.4 0.2 0 6 12 18 24 # at risk 30 36 42 48 71 59 33 20 16 11 6 3 1 77 68 43 24 12 7 7 4 0 59 58 47 40 34 24 15 6 2 Minimal Moderate Extensive FIGURE 3.  Kaplan-Meier survival analysis of time from first treatment to recurrence by severity of presenting condyloma.
  8. 8. Diseases of the Colon Rectum Volume 57: 6 (2014) 759 than 1 treatment for clearance, but had no effect on re- currence after achieving primary clearance. Some studies have shown that posttreatment imiquimod as an adjuvant reduces recurrence in both men and women with ano- genital condyloma.25–27 On the surface, our data, however, seem contradictory. An explanation for this seemingly op- posite finding is that imiquimod use in our cohort was significantly associated with the severity of disease, and, as such, our results likely reflect imiquimod as a proxy for more significant disease, rather than an independent fac- tor for causing recurrence. Further study is necessary to determine the true relationship between imiquimod and recurrence. Almost one-third of patients who achieved clearance had a recurrence, a rate that is similar to rates reported in other series.10–12,28 It is noteworthy that the median time from first treatment to recurrence was more than 2 years; some patients did not have a recurrence until 3 or more years. Some “recurrence” may be related to new infection rather than to the recurrence of disease present at the time of primary therapy; we cannot determine if this was in- deed the case, because our data did not capture whether participants who had a later recurrence differed in sexual practices or numbers of partners than those who did not have a recurrence. Our data did not identify any significant variable as- sociated with recurrence, including severity or location of disease, or method of treatment. Other series have associ- ated smoking with recurrence, but we did not find that to be the case.29 Our data also did not show that those with the most extensive disease or requiring multiple treat- ments to achieve primary clearance were the most likely to have a recurrence and may be due to assumptions made in our study design: specifically, that we did not begin cal- culating recurrence until patients were clear for 4 months. Moreover, the multiple treatments required by some (those with more extensive disease and with both perianal and intraanal condyloma) could actually have been treat- ing recurrent rather than primary disease. If this is the case, then our data actually show that there are no obvi- ous variables affecting recurrence once a patient has been disease free for 4 months. Although it would seem intuitive that participants with minimal disease would take longer to have a re- currence than those with more extensive disease, our ­Kaplan-Meier curves of time to recurrence show no dif- ference in time to recurrence for those with minimal and extensive disease, and those with moderate disease had significantly faster recurrences and were more likely to re- quire more than 1 treatment to achieve primary clearance (Fig. 3). This finding may be a reflection of the somewhat subjective method by which we grouped patients based on disease severity, and some classified as moderate disease might actually have had extensive disease. Another possi- ble explanation is that those with extensive disease had cir- cumferential or near-circumferential ablation. This more extensive ablation might have decreased recurrence over those with only moderate disease where condyloma-free skip areas were not treated. Leaving areas untreated might have predisposed these patients to recurrence because of less aggressive therapy. Further study is necessary to an- swer this question. Moreover, it would be ideal to develop and validate a more exact measurement for reporting se- verity of disease in future investigations. In addition, as demonstrated in other studies, our data support that HIV-negative MSM with condyloma are at risk for HSIL, an anal cancer precursor.15,30 Our findings reinforce the importance of evaluating patients with con- dyloma for HSIL with HRA and biopsy of areas suspicious for HSIL. Condyloma must be viewed as a marker of HPV infection—both LR and oncogenic HPV. It is difficult to draw definitive conclusions from our data regarding factors associated with failure to achieve primary clearance postablation given the small number of participants that fell into this category. That said, it ap- pears that shorter duration of follow-up and not receiv- ing qHPV could make patients less likely to clear. With only 1 participant who did not achieve clearance having just intra-anal condyloma, it is dangerous to apply much import to that as a significant trait associated with failure to clear. More study needs to be done with a much larger sample size and longer follow-up to determine what char- acteristics, if any, are associated with the inability to clear condyloma. This study has a number of limitations in addition to those already mentioned. First, it is a retrospective analysis of prospectively collected data in a highly select group of MSM treated by a surgeon experienced in treat- ing ­HPV-related anorectal disease; as such, the data might not be generalizable to other populations. The analysis also excluded patients who did not achieve primary clear- ance and those who had inadequate follow-up, and these patients significantly differed from patients who were ana- lyzed in 2 key ways. Additionally, this analysis combined those who received qHPV before treatment and those who received qHPV concurrent with treatment into a single group that may have obscured differences between those 2 groups. Further, flat LSIL was also not included in the analysis and this could have caused an underestimation of recurrence. The time interval between wart appearance and the initiation of treatment was not evaluated, because it is highly subjective. There is no way to know how long a patient had disease before it was actually identified. The interval between disease appearance and treatment may have influenced disease severity, treatment effectiveness, or recurrence. Additionally, our classification of lesions by visual inspection constitutes a subjective variable that may have affected our final analysis. Finally, data regarding smoking history and sexual practices were only collected at the initial visit, and, based on our data, we cannot evalu-
  9. 9. SILVERA ET AL: CONDYLOMA AMONG HIV-NEGATIVE MSM760 ate how changes in those habits may affect treatment or recurrence. The strengths of this study include the fact that it is one of the few to examine the efficacy of condyloma treatment in MSM with anal canal disease. Moreover, the lengthy follow-up can give a truer estimate of probabil- ity of recurrence than most studies with a much shorter follow-up. CONCLUSION Most HIV-negative MSM with anorectal condyloma can achieve primary clearance with 1 treatment with the use of laser or cautery ablation. Those with more extensive disease are more likely to require multiple treatments to achieve clearance. Approximately one-third of patients treated had a recurrence, but the time to recurrence was long. No obvious variables affecting recurrence were identified. REFERENCES 1. Centers for Disease Control and Prevention. Genital HPV In- fection - Fact Sheet. 2013:2.Available ­at:http://www.cdc.gov/std/ HPV/HPV-Factsheet-March-2013.pdf. 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