1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 SUPPLEMENTARY MATERIAL Progression, regression, and clearance of HPV6/11 infections Per the study design and a limitation of this analysis, swabs were not tested for HPV types 6 and 11 beyond the first three trial visits in Protocol 012. Thus, it was not possible to provide direct estimates of the proportion of HPV-6 and 11 infections clearing, persisting, and progressing to VIN over time. To provide some sense for the risk of developing VIN following incident HPV-6 or 11 infection, an alternate methodology from that described above for HR types was employed. The analyses included data from the placebo arm of protocol 012, as well as the placebo arms of Protocols 011 and 015. For protocols 011 and 012, women with negative HPV-6 or 11 results on their first two LVPP swabs, and with a subsequent swab specimen positive for HPV-6 or 11 (typically on their third swab) were selected for analysis of incident HPV-6 and 11 infections. Women lacking a swab sample positive for HPV-6 or 11, but who tested positive for one of these HPV types on an external genital biopsy specimen between the dates of their second and third swabs were also selected for analysis. The date of the incident HPV infection for these women was defined as above for HR types. In protocol 015, because only two swab samples were generally collected for each woman (day 1 and month 7), only one negative swab sample was required for defining an incident HPV-6 or 11 infection. Women developing a VIN lesion following incident HPV-6 or HPV-11 infection were evaluated in a manner similar to that described for HR HPV types. However, unlike the preceding analyses where women could also reach an endpoint of infection "clearance" due to the absence of HPV DNA in LVPP swabs following an incident HPV infection, it was not possible to evaluate clearance of HPV-6 and 11 infections due to the lack of swab testing throughout the trials. Therefore, all other women were evaluated as censored as of the date of their last routine visit. 1
24 25 26 27 28 29 30 31 32 33 34 35 Incidence rates of HPV-6 and 11 infections were 3.3 and 1.5 per 100 person years, respectively (Table S1). Due to the lack of testing for HPV-6 and HPV-11 during the trial, data for these low-risk types are based on an average of seven months of follow-up post day 1. Cumulative progression rates of HPV-6 and 11 infections to VIN1 and VIN2/3 by time point are reported in Table S2. The mean time from incident HPV 6- or HPV-11 infection (generally based on the first 2 or 3 trial swabs only) to the development of VIN was 9.4 months (95%CI: 8.4-10.4). After a statistical adjustment that assumes a fractional allocation for each individual HPV type, the 36-month risk of progression of incident HPV-11 infections to VIN2/3 declined from 2.7% to 0.0%, as HPV-11 was only observed in combination with HPV-16, but never in isolation. Across 208 incident HPV-6 and 11 infections, 3 women developed a VIN lesion positive for the same HPV type. One VIN2/3 lesion tested positive for HPV-11 and HPV-16, and two VIN1 lesions tested positive for HPV-6 only (Table S3). 36 37 38 39 40 41 42 43 44 45 46 47 48 2
49 50 Table S1. Incidence rates of HPV 6 and 11 infections (Protocols 011, 012 and 015). Number of Mean Incidence per incident VIN HPV Number Number exposure Cases/Person- 100 person- lesions by type eligible excluded (%) time, years years years grade 6 1,600 59 (3.6%) 0.4 19/578 3.3 NA 11 1,655 7 (0.4%) 0.4 9/601 1.5 NA 51 52 A woman is counted only once in each row. A woman may appear in more than one row. For HPV-6 and HPV-11, data are based on an average of seven months of follow-up post day 1. 53 54 55 56 57 58 59 60 61 62 63 64 3
65 Table S2. Progression to VIN and clearance of incident external genital HPV type 6 and 11 infections (Protocol 011, 012 and 015). Mean available Non-adjudicated Non-adjudicated Adjudicated Adjudicated observation Persisting Clearing window, (95% CI) (95% CI) months VIN1 (95% CI) VIN2/3 (95% CI) VIN1 (95% CI) VIN2/3 (95% CI) HPV 6 (n = 171) 39.9 12 Months -- NA NA 1.2 (0.0-2.8) 0.0 (-) 1.2 (0.0-2.8) 0.0 (-) 24 Months -- NA NA 1.2 (0.0-2.8) 0.0 (-) 1.2 (0.0-2.8) 0.0 (-) 36 Months -- NA NA 1.2 (0.0-2.8) 0.0 (-) 1.2 (0.0-2.8) 0.0 (-) HPV 11 (n = 37) 39.0 NA NA 12 Months -- NA NA 0.0 (-) 2.7 (0.0-7.9) 0.0 (-) 0.0 (-) 24 Months -- NA NA 0.0 (-) 2.7 (0.0-7.9) 0.0 (-) 0.0 (-) 36 Months -- NA NA 0.0 (-) 2.7 (0.0-7.9) 0.0 (-) 0.0 (-) 66 67 68 69 n = number of incident infections. A woman is counted only once for each HPV type. A woman may have an incident infection with more than one HPV type. CI = Confidence Interval; NA = Not Applicable, as HPV testing data for swabs were generally not available for HPV types 6 and 11 beyond the first three trial visits and persistence/clearance of infection could not be evaluated. 70 71 72 4
73 Table S3. HPV type distribution across VIN lesions arising from incident infections (Protocols 011, 012, 015). Subject # Lesion Grade HPV type Treatment 10 VIN 2/3 11, 16 Not available * 11 VIN 1 6 Not available * 12 VIN 1 6 Not available * 74 75 * All three HPV-6/11 lesions were diagnosed in Protocol 015, a protocol where treatments for VIN were not recorded. 76 77 78 5