NIH Public Access Author Manuscript J Low Genit Tract Dis. Author manuscript; available in PMC 2014 April 01.

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1 NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript NIH Public Access Author Mauscript J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01. Published i fial edited form as: J Low Geit Tract Dis April ; 17(5 0 1): S69 S77. doi: /lgt.0b013e b1. Follow-up testig post-colposcopy: Five-year risk of CIN2+ after a colposcopic diagosis of CIN1 or less Hormuzd A. Katki, Ph.D. 1,*, Julia C. Gage, Ph.D., M.P.H. 1, Mark Schiffma, M.D., M.P.H. 1, Philip E. Castle, Ph.D., M.P.H. 2, Barbara Fetterma, SCT (ASCP) 3, Nacy E. Poitras, P.M.P. 3, Thomas Lorey, M.D. 3, Li C. Cheug, M.S. 4, Tia Raie-Beett, M.D., M.P.H. 5, ad Walter K. Kiey, M.D. 6,* 1 Divisio of Cacer Epidemiology ad Geetics, Natioal Cacer Istitute, Natioal Istitutes of Health, DHHS, Bethesda, MD, USA 2 Visitig Professor, Albert Eistei College of Medicie, The Brox, NY, USA 3 Regioal Laboratory, Kaiser Permaete Norther Califoria, Berkeley, CA, USA 4 Iformatio Maagemet Services, Ic., Calverto, MD, USA 5 Wome s Health Research Istitute, Divisio of Research, Kaiser Permaete Norther Califoria, Oaklad, CA, USA 6 Divisio of Gyecologic Ocology, Kaiser Permaete Medical Care Program, Oaklad, CA, USA Abstract Objective The majority of wome referred for colposcopy are ot diagosed with CIN2+ but, oetheless, are typically asked to retur much sooer tha their ext routie screeig iterval i 3-5 years. A importat questio is how may subsequet egative Pap results, or egative Pap ad HPV cotest results, are eeded prior to returig to a exteded retestig iterval. Methods We estimated 5-year risks of CIN2+ for 3 follow-up maagemet strategies after colposcopy (Pap-aloe, HPV-aloe ad cotestig) for 20,319 wome aged 25 ad older screeed from at Kaiser Permaete Norther Califoria who were referred for colposcopy but for whom CIN2+ was ot iitially diagosed (i.e., Wome with CIN1/egative colposcopy ). Results Screeig results immediately atecedet to CIN1/egative colposcopy iflueced subsequet 5-year CIN2+ risk: wome with a atecedet HPV-positive/ASC-US or LSIL Pap had a lower risk (10%) tha those with atecedet ASC-H (16%, p<0.0001) or HSIL+ (24%, p<0.0001). For wome with a atecedet HPV-positive/ASC-US or LSIL, a sigle egative * Correspodig authors:hak: Divisio of Cacer Epidemiology ad Geetics, Natioal Cacer Istitute, 6120 Executive Blvd. Room 8014, EPS MSC 7244, Bethesda, MD 20882, Phoe: , Fax: , katkih@mail.ih.govwkk: Kaiser Permaete Norther Califoria, Sacrameto Medical Ceter, 1650 Respose Road, Sacrameto, CA 95815, Phoe: , walter.kiey@kp.org. Coflicts of Iterest: Dr. Schiffma ad Dr. Gage report workig with Qiage, Ic. o a idepedet evaluatio of o-commercial uses of CareHPV (a low-cost HPV test for low-resource regios) for which they have received research reagets ad techical aid from Qiage at o cost. They have received HPV testig for research at o cost from Roche. Dr. Castle has received compesatio for servig as a member of a Data ad Safety Moitorig Board for HPV vaccies for Merck. Dr. Castle has received HPV tests ad testig for research at a reduced or o cost from Qiage, Roche, MTM, ad Norchip. Dr. Castle is a paid cosultat for BD, GE Healthcare, ad Cepheid, ad has received a speaker hoorarium from Roche. No other authors report ay coflicts of iterest. This is a PDF file of a uedited mauscript that has bee accepted for publicatio. As a service to our customers we are providig this early versio of the mauscript. The mauscript will udergo copyeditig, typesettig, ad review of the resultig proof before it is published i its fial citable form. Please ote that durig the productio process errors may be discovered which could affect the cotet, ad all legal disclaimers that apply to the joural pertai.

2 Katki et al. Page 2 NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript cotest approximately 1 year post-colposcopy predicted lower subsequet 5-year risk of CIN2+ (1.1%) tha 2 sequetial egative HPV tests (1.8%, p=0.3) or 2 sequetial egative Pap results (4.0%, p<0.0001). For those with a atecedet ASC-H or HSIL+ Pap, 1 egative cotest after 1 year predicted lower subsequet 5-year risk of CIN2+ (2.2%) tha 1 egative HPV test (4.4%, p=0.4) or 1 egative Pap (7.0%, p=0.06); isufficiet data existed to calculate risk after sequetial egative cotests for wome with high grade atecedet cytology. Coclusios After CIN1/egative colposcopy followed by egative post-colposcopy tests, wome did ot achieve sufficietly low CIN2+ risk to retur to 5-year routie screeig. For wome with atecedet HPV-positive/ASC-US or LSIL, a sigle egative post-colposcopy cotest reduced risk to a level cosistet with a 3-year retur. For wome with atecedet ASC-H or HSIL+, o sigle egative test result sufficed to reduce risk to a level cosistet with a 3-year retur. Precis For wome with CIN1/egative colposcopy ad atecedet HPV-positive/ASC-US or LSIL, a sigle egative post-colposcopy cotest reduced risk to a level cosistet with a 3-year retur. Keywords Huma Papillomavirus (HPV); cacer prevetio; Pap; cervical itraepithelial eoplasia (CIN); Hybrid Capture 2 (HC2); colposcopy Itroductio I the US, few wome referred to colposcopy are diagosed immediately with histologically cofirmed cervical itraepithelial eoplasia grade 2 (CIN2) or worse (CIN2+) that requires treatmet. This is because may wome are referred to colposcopy for LSIL or HPVpositive/ASC-US, rather tha higher-risk screeig results, such as ASC-H or HSIL. Recet chages i screeig guidelies (1, 2) that icorporate cotestig recommed that wome with persistet HPV-positive/Pap-egative results also should be referred to colposcopy, further icreasig the umber of colposcopic examiatios that will result i CIN1 or egative colposcopic diagoses (beig colposcopic appearace, or a egative or CIN1 biopsy). The 2006 maagemet guidelies recommed repeat testig at 6 or 12 moth itervals (3) for wome with a CIN1/egative colposcopy diagosis. While laborious, such heighteed surveillace is warrated because, compared with the geeral populatio, these wome remai at elevated risk of beig diagosed with subsequet CIN2+ (4-7). However, most wome with a ormal colposcopic impressio or ormal/cin1 histology will ever develop CIN2+ (6) ad therefore should retur to routie screeig at some poit. Cotiued itesive surveillace of these wome ca ofte fid mior abormalities that would aturally resolve without treatmet. But, sice the discovery of mior abormalities misplaces wome ito a higher risk category that justifies eve more surveillace, it is icreasigly difficult to ever retur them to a routie screeig schedule. Cosequetly, the resultat questio i patiet maagemet is to defie a sufficiet umber of egative follow-up tests that will provide assurace that a woma is safe for retur to routie screeig or, at least, to exteded retestig itervals. The 2006 ASCCP maagemet guidelies for wome with a CIN1 or egative colposcopy provide recommedatios for retur to routie screeig by the referrig (i.e., atecedet ) Pap result, because the risk of a udetected or icipiet CIN2+ is expected to be greater i wome with a atecedet HSIL or greater Pap result tha i wome with a ASCUS or LSIL Pap (3). Uder the curret guidelies, wome with CIN1 preceded by HSIL or greater Pap results ca retur to J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01.

3 Katki et al. Page 3 NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript Methods routie cytologic screeig at 3 years, after 2 egative colposcopy ad Pap results. Wome with CIN1 preceded by ASC-US, ASC-H or LSIL ca retur to routie cytologic screeig after either 2 Pap-egative tests at 6-moth itervals or 1 HPV-egative test at 1 year. (Of ote, ASC-H was combied with ASC-US ad LSIL i the 2006 recommedatios.) However, the 2006 recommedatios were largely based upo expert opiio because oly limited data were available (6). Furthermore, the 2006 recommedatios did ot provide guidace o the use of cotestig for follow-up post-colposcopy. Data from Kaiser Permaete Norther Califoria (KPNC), a large itegrated health system that routiely performs cotestig for both screeig ad some aspects of follow-up maagemet, are ow available to estimate more accurately the risks of subsequet CIN2+ i wome followig a CIN1 or egative colposcopy. I this mauscript, we evaluate the risks of CIN2+ i post-colposcopic maagemet of wome without iitial evidece of CIN2, with cosideratio of their atecedet Pap ad follow-up Pap ad cotest results. The desig of our cohort study from KPNC has bee described previously (8); i this report we elarged the dataset from wome age to iclude all wome age 25 ad older, screeed from 2003 to 2010, i order to icrease the umbers of wome with postcolposcopy iformatio. Data o histologic outcomes were collected o all wome through December 31, The Kaiser Permaete Norther Califoria Istitutioal Review Board (IRB) approved use of the data, ad the Natioal Istitutes of Health Office of Huma Subjects Research deemed this study exempt from IRB review. The Permaete Medical Group (TPMG) develops Cliical Practice Guidelies for cervical cacer screeig ad maagemet of abormal tests i partership with the KP Natioal Guidelie Program, Care Maagemet Istitute, to support cliical decisios of their providers. Accordig to guidelies, wome with HPV-positive/ASC-US, or with LSIL or worse Pap results, should udergo colposcopy. Per KPNC guidelies, at least 1 biopsy is take at the great majority of colposcopy examiatios to improve the sesitivity. Therefore, histological results are available for most wome referred for colposcopy. For wome with a CIN1/egative colposcopy, KPNC guidelies are virtually idetical to those of ASCCP; i practice at KPNC cotestig, rather tha Pap or HPV tests aloe, is the predomiat mode of screeig ad follow-up testig. Whe risk was calculated for a cytology result without regard to HPV testig, or vice versa, we refer to those risks as Pap-aloe or HPV-aloe. Pap tests were performed at KPNC regioal ad facility labs. Covetioal Pap slides were maually reviewed followig processig by the BD FocalPoit Slide Profiler (BD Diagostics, Burligto, NC, USA) primary screeig ad directed quality cotrol system, i accordace with FDA-approved protocols. Startig i 2009, KPNC trasitioed to liquidbased Pap testig usig BD SurePath (BD Diagostics, Burligto, NC, USA). Covetioal or liquid-based Pap tests are reported accordig to the 2001 Bethesda System(9). HPV tests were performed oly i the KPNC regioal lab. Hybrid Capture 2 (HC2; Qiage, Germatow, MD, USA) was used to test for high-risk HPV types accordig to maufacturer s istructios. Figure 1 provides a descriptio of the study populatio. This aalysis was limited to wome with a baselie Pap ad/or cotest screeig result (called atecedet scree ) that would trigger referral for colposcopy: HPV-positive/ASC-US, LSIL, AGC, ASC-H, HSIL, or SCC. We the excluded from the aalysis wome who had a CIN2+ biopsy result at the colposcopy triggered by the screeig results. Because we wished to defie risk after follow-up testig, we also omitted wome without further follow-up testig (either Pap- J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01.

4 Katki et al. Page 4 aloe or cotests). Fially, wome were excluded i the rare occasio that they were treated after the atecedet scree but before a biopsy result. NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript Results Therefore, the wome who remaied i this aalysis had (1) a biopsy result of CIN1 or ormal/metaplasia, (2) a ormal colposcopy without biopsy or (3) o colposcopy betwee the atecedet abormal scree that would trigger referral to colposcopy ad the follow-up Pap or cotest. We are uable to distiguish the wome i groups (2) ad (3) because this aalysis is based upo histology records. We therefore chose to iclude them because a chart review of KPNC colposcopy records showed that the majority of wome fell ito group (2), havig had colposcopy before their subsequet follow-up test. By defiitio, wome i this cohort were ot diagosed with CIN2+ before follow-up testig. Therefore, the cumulative risk of CIN2+, CIN3+, or cervical cacer was calculated as the sum of risk at the first follow-up test after the atecedet scree (plotted at time zero o each figure) ad the icidece followig the first follow-up test (8). The results were stratified by wome s atecedet screeig results. Although the majority of wome uderwet cotestig, we disaggregated results ad the compared 3 maagemet strategies to follow-up wome post-colposcopy: Pap-aloe, HPValoe, ad cotestig. All Pap ad HPV test results from up to 2 cosecutive follow-up tests were used to idetify wome testig egative at follow-up uder a give strategy (e.g., all Pap results were icluded i the Pap-aloe strategy, regardless if the Pap test was part of a cotest or ot). I a acillary aalysis (data ot show), we verified that the risks calculated based o this Pap-aloe defiitio were similar to risks from a Pap-aloe strategy with o HPV test. The cumulative 5-year CIN2+ risks were calculated for wome who had egative follow-up test results for each of the 3 maagemet strategies. The 5-year CIN2+ risks are calculated startig from the date of the last egative follow-up test (i.e., the risk after the 1 st follow-up test for 1 egative Pap result, the risk after the 2 d follow-up test for 2 cosecutively egative Pap results). I geeral, we focused o risk of CIN2+ for this aalysis because we had too few CIN3+ evets to estimate reliably the CIN3+ risks. Whe zero icidet CIN2+ evets occurred, o exact p-value or cofidece iterval could be calculated, so we calculated coservative cofidece itervals by calculatig the right-edpoit of the cofidece iterval with 1 CIN2+ evet ad ivertig this iterval to obtai p-values whe eeded. We idetified 20,319 wome with a biopsy result of CIN1/egative or presumed ormal colposcopy exam ad subsequet follow-up tests (Figure 1). Table 1 shows the data used i the followig aalyses, specifically the distributio, by atecedet Pap or cotest result, of the worst histologic fidigs through 2010, for all wome with CIN1/egative colposcopy. Atecedet screeig results predicted subsequet risk. Most (84%) of the atecedet Pap/ cotest results were lesser abormalities (HPV-positive/ASC-US, LSIL) but a miority (38%) of the 34 cacers occurred i these wome. The proportios of CIN2+ diagoses durig follow-up that were CIN3/AIS or cacer (CIN3+) also differed by atecedet screeig result: the proportios of CIN3+ diagoses were higher for wome with a atecedet ASC-H or HSIL+ Pap (47.7% CIN3/AIS ad 6.5% cacer) tha for wome with a atecedet HPV-positive/ASC-US cotest or LSIL Pap (CIN3/AIS: 34.7%, p<0.0001; Cacer: 1.4%, p<0.0001). The proportio of cacer followig a atecedet AGC Pap (14.0%) was greater tha that followig ASC-H or HSIL+ (6.5%, p=0.1) or lesser abormalities, (1.4%, p<0.0001). J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01.

5 Katki et al. Page 5 NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript Figure 2 shows the overall risks of subsequet CIN2+, CIN3+, ad cacer followig a CIN1/egative colposcopy, stratified by atecedet Pap/cotest. Wome with a CIN1/ egative colposcopy had substatially reduced CIN2+ risks for each Pap/cotest result relative to the risks prior to colposcopy (8). However, wome with high-grade atecedet Pap results cotiued to have elevated 5-year risks for CIN2+ (24% for wome with a atecedet HSIL or worse, compared with 10% for wome with HPV+/ASC-US or LSIL). Moreover, wome with a atecedet HPV-positive/ASC-US or LSIL had a 0.17% 5-year cacer risk, cosiderably lower tha rates for wome with high-grade screeig abormalities (AGC:0.77%, p=0.006; ASC-H:1.6%, p=0.0002; HSIL+: 2.1%, p<0.0001). Table 2 shows the actual umber of wome who had a egative Pap, HPV or cotest result at subsequet follow-up tests. Amog wome with atecedet HPV-positive/ASC-US or LSIL, 5939 were followed with cotestig, 5450 were followed with Pap aloe ( ), ad 1031 were followed with HPV aloe ( ). Amog wome with atecedet AGC/ ASC-H/HSIL+, 1501 were followed with cotestig, 683 were followed with Pap aloe, ad 248 were followed with HPV aloe. Figure 3 shows CIN2+ risks followig egative follow-up tests for wome with CIN1/ egative colposcopy ad atecedet HPV-positive/ASC-US or LSIL uder 3 maagemet strategies (Pap-aloe, HPV-aloe ad cotestig). With 2 egative follow-up tests, the subsequet 5-year CIN2+ risk teded to decrease but oly slightly (1 egative Pap result vs. 2 egative Pap result: 5.4% vs. 4.0% (p=0.08)); 1 egative HPV test vs. 2 egative HPV tests: 2.0% vs. 1.8% (p=0.9); 1 egative cotest vs. 2 egative cotests: 1.1% vs. 1.0% (p=0.9)). Most importatly, a sigle egative cotest coferred lower subsequet 5-year risk of CIN2+ (1.1%; 95%CI: 0.7% to 1.9%) tha 2 egative HPV tests (1.8%, p=0.3) or 2 egative Pap results (4.0%, p<0.0001). Figure 4 shows CIN2+ risks for wome followig egative follow-up tests amog wome with CIN1/egative colposcopy ad atecedet ASC-H/HSIL+ or AGC uder 3 maagemet strategies (Pap-aloe, HPV-aloe ad cotestig). A sigle egative cotest coferred lower risk tha a sigle egative HPV test or Pap test. For ASC-H/HSIL+ atecedet Paps, the lowest CIN2+ risk occurred after 1 egative cotest (2.2%, 95%CI 0.7% to 6.9%) rather tha 1 egative HPV test (4.4%, p=0.4) or a sigle egative Pap (7.0%, p=0.06). For atecedet AGC Pap results, the lowest CIN2+ risk agai occurred after 1 egative cotest (0%, 95%CI 0% to 3.4%) versus 1 egative HPV test (0.58%, p=0.09) or 1 egative Pap (1.7%, p=0.07). We had isufficiet umbers to address 2 cosecutively egative follow-up tests with atecedet ASC-H/HSIL+ or AGC. Table 3 bechmarks 5-year CIN2+ risk for egative follow-up tests after CIN1/egative colposcopy for atecedet HPV-positive/ASC-US or LSIL to the risk thresholds for maagemet of screeig Pap test results (8). Post-colposcopy Pap-egative risks were similar to those that i the screeig cotext etail a 6-12 moth retur, such as ASCUS (6.9%). The post-colposcopy HPV-egative risks were itermediate betwee risk thresholds for a 1- ad 3-year retur. The post-colposcopy egative cotest risks were similar to risk thresholds for a 3-year retur, i particular, the 0.68% 5-year CIN2+ risk amog screeig Pap-egative wome. However, o egative test result followig CIN1/egative colposcopy ever reached the ultra-low risk threshold of 0.27% 5-year CIN2+ risk curretly required for a 5-year retur. Table 4 bechmarks 5-year CIN2+ risk for egative follow-up tests after CIN1/egative colposcopy for atecedet ASC-H/HSIL+ or AGC to the risk thresholds for maagemet of screeig test results. For atecedet ASC-H/HSIL+, oe of the follow-up test strategies had a risk approachig the implicit risk for Pap-egative results (0.68%) for which a 3-year J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01.

6 Katki et al. Page 6 NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript Discussio retur is recommeded (10). For AGC, 1 egative HPV test had a risk of 0.58% (95%CI: 0.1% to 2.3%), similar to the 3-year retur threshold, although the cofidece iterval was wide. The risk estimate for wome with a egative cotest was ucertai due to sparse outcome data. Of ote, ulike CIN2+ risks, the cacer risks with atecedet AGC were high (1 egative Pap had a risk of 0.18% (95%CI: 0.02% to 1.4%) ad 1 egative HPV test had a risk of 0.38% (95%CI: 0.05% to 2.7%)) which were comparable to the cacer risks after screeig results of LSIL (0.16%) or HPV-positive/ASC-US (0.41%) for which immediate colposcopy is recommeded (10). Our data suggest that havig a CIN1/egative colposcopy lowers 5-year risk of CIN2+ amog wome with abormal screeig tests referred to colposcopy; however, substatial risk remais. For wome referred for colposcopy for HPV-positive/ASC-US or LSIL, a sigle egative cotest after CIN1/egative colposcopy cofers substatial reassurace agaist subsequet CIN2+. I cotrast, for wome referred for colposcopy for AGC/ASC-H/ HSIL+, a sigle egative Pap/HPV/cotest appears to cofer less reassurace agaist CIN2+. Ufortuately, o sequece of egative tests after colposcopy for ay idicatio reduces CIN2+ risk to a level sufficietly safe to retur to 5-year screeig itervals. Still, cotestig provides the most reassurace with the fewest umber of follow-up tests. The majority (84%) of wome with a CIN1 or egative colposcopy had a low-grade atecedet screeig result (HPV-positive/ASC-US or LSIL). Followig a sigle egative cotest, their risk was reduced to a level sufficietly low to cosider a 3-year retur. Notably, a sigle egative cotest provided more reassurace agaist CIN2+ tha 2 egative HPV tests or 2 egative Paps. A similar relatioship was reported i the ASCUS LSIL Triage Study (ALTS), i which the 2-year CIN2+ risks were higher overall: 1.8% after 1 follow-up egative cotest, 2.4% after a follow-up HPV-egative test ad 4.6% after a follow-up egative Pap (11). A secod egative cotest did ot add additioal risk reductio over a sigle egative cotest. I the KPNC populatio, 46% of wome with a low-grade atecedet screeig result, followed with cotestig, were egative at their first follow-up test, suggestig that perhaps up to half of these wome could be spared yearly itesive colposcopy ad retured to a 3-year testig iterval. A miority (16%) of wome with a CIN1 or egative colposcopy had a high grade atecedet screeig result (AGC, ASC-H, or HSIL+), but a majority (62%) of the cacers occurred i these wome. No sigle egative test result coferred low eough risk to cosider a 3-year rather tha a 1-year retur; ufortuately, isufficiet data existed to calculate risk after more tha 1 egative test result. For wome with atecedet AGC, although few CIN2 were diagosed after a subsequet egative test result, the cacer risk remaied high, justifyig maagig AGC similarly to ASC-H or HSIL+. Ideally, a radomized trial comparig 3 follow-up strategies after a CIN1/egative histology, or egative colposcopy (Pap-aloe, HPV-aloe or cotestig) would best idetify the correct maagemet to determie whe it is safe for a woma to retur to routie screeig. I the absece of such a study, we aalyzed observatioal data from a large itegrated health system that utilizes cotestig. There are importat limitatios to this aalysis. Because fidigs were similar, we combied CIN1 with ormal biopsy ad also combied some atecedet screeig test results. Due to few outcomes, we were uable to characterize the risks of wome referred to colposcopy for repeat HPV-positive/Pap-egative screeig cotests. We did ot have eough iformatio to cosider the effect of age, so we combied all wome age 25 ad older. J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01.

7 Katki et al. Page 7 NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript Ackowledgmets Refereces I additio, our aalytic sample was defied by histology records, so that i the absece of a biopsy result, we were uable to distiguish betwee wome with a ormal colposcopy without biopsy vs. wome missig colposcopy betwee their atecedet scree ad followup test. For atecedet HSIL+, 15% were without biopsy, but for other screeig abormalities 30-40% were without biopsy. Chart reviews suggested that most wome likely had a colposcopy exam betwee their screeig abormality ad follow-up test. We have assumed that, give the low risk of CIN2+ betwee a baselie scree ad later ormal Pap or cotest, almost all wome missig colposcopy would have had a CIN1/egative result (especially if their future Pap/HPV/cotest was egative). A acillary aalysis of wome without biopsy results showed similar 5-year CIN2+ risks compared to wome with CIN1 or egative biopsy results. Fially, our aalysis estimated CIN2+ risks after egative follow-up Pap results take from either Pap tests aloe or i the cotext of cotestig. It is likely that wome with a HPVpositive/Pap-egative cotest are followed more closely tha a Pap-egative test aloe, thereby detectig more CIN2+ ad likely overestimatig the short-term risks after a egative Pap. However, we assumed that Pap-aloe would likely have idetified withi 5 years ay true persistet treatable lesio foud earlier by cotestig, so we focused o 5-year risk calculatios. The oly defiitive way to resolve this issue would be a trial to radomize wome to cotestig versus Pap-aloe. Our fidigs suggest that cotestig may be better tha Pap-aloe or HPV-aloe testig for followig wome after colposcopy. More data are required to determie how may more egative cotests are required to permit returig wome to routie 5-year screeig, especially for wome referred for colposcopy by high-grade Pap tests ad ot iitially foud to have CIN2+. Role of the fudig source The fudig sources did ot review or approve the study desig ad were ot ivolved i data collectio, aalysis, iterpretatio, or i writig the paper. The Itramural Research Program of the US Natioal Istitutes of Health/Natioal Cacer Istitute ad Kaiser Permaete Norther Califoria reviewed the fial mauscript for publicatio. The Kaiser Permaete Norther Califoria Istitutioal Review Board (IRB) approved use of the data, ad the Natioal Istitutes of Health Office of Huma Subjects Research deemed this study exempt from IRB review. 1. Moyer VA. Screeig for cervical cacer: U.S. Prevetive Services Task Force recommedatio statemet. A Iter Med. 2012; 156(12): W312. [PubMed: ] 2. Saslow D, Solomo D, Lawso HW, Killackey M, Kulasigam SL, Cai JM, et al. America Cacer Society, America Society for Colposcopy ad Cervical Pathology, ad America Society for Cliical Pathology screeig guidelies for the prevetio ad early detectio of cervical cacer. J Low Geit Tract Dis. 2012; 16(3): [PubMed: ] 3. Wright TC Jr. Massad LS, Duto CJ, Spitzer M, Wilkiso EJ, Solomo D cosesus guidelies for the maagemet of wome with cervical itraepithelial eoplasia or adeocarcioma i situ. J Low Geit Tract Dis. 2007; 11(4): [PubMed: ] 4. Ostor AG. Natural history of cervical itraepithelial eoplasia: a critical review. It J Gyecol Pathol. 1993; 12(2): [PubMed: ] 5. Melikow J, Nuovo J, Willa AR, Cha BK, Howell LP. Natural history of cervical squamous itraepithelial lesios: a meta-aalysis. Obstet Gyecol. 1998; 92(4 Pt 2): [PubMed: ] 6. Cox JT, Schiffma M, Solomo D. Prospective follow-up suggests similar risk of subsequet cervical itraepithelial eoplasia grade 2 or 3 amog wome with cervical itraepithelial eoplasia J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01.

8 Katki et al. Page 8 NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript grade 1 or egative colposcopy ad directed biopsy. Am J Obstet Gyecol. 2003; 188(6): [PubMed: ] 7. Pretorius RG, Peterso P, Azizi F, Burchette RJ. Subsequet risk ad presetatio of cervical itraepithelial eoplasia (CIN) 3 or cacer after a colposcopic diagosis of CIN 1 or less. Am J Obstet Gyecol. 2006; 195(5): [PubMed: ] 8. Katki HA, Schiffma M, Castle PE, Fetterma B, Poitras NE, Lorey T, et al. Bechmarkig CIN3+ risk as the basis for icorporatig HPV ad Pap cotestig ito cervical screeig ad maagemet guidelies. J Low Geit Tract Dis. Submitted. 9. Solomo D, Davey D, Kurma R, Moriarty A, O Coor D, Prey M, et al. The 2001 Bethesda System: termiology for reportig results of cervical cytology. JAMA. 2002; 287(16): [PubMed: ] 10. Katki HA, Schiffma M, Castle PE, Fetterma B, Poitras NE, Lorey T, et al. Five-year risk of cervical cacer ad CIN3 for HPV-positive ad HPV-egative high-grade Pap results. J Low Geit Tract Dis. To be submitted. 11. Walker JL, Wag SS, Schiffma M, Solomo D. Predictig absolute risk of CIN3 durig postcolposcopic follow-up: results from the ASCUS-LSIL Triage Study (ALTS). Am J Obstet Gyecol. 2006; 195(2): [PubMed: ] J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01.

9 Katki et al. Page 9 NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript Figure 1. Diagram of wome with CIN1/egative colposcopy J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01.

10 Katki et al. Page 10 NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript Figure 2. Cumulative risk of CIN2+ (Left Pael), CIN3+ (Middle Pael), ad cacer (Right Pael) followig CIN1/egative colposcopy give atecedet HSIL+, ASC-H, AGC, ad HPVpositive/ASC-US or LSIL, amog wome aged 25 ad older. Note that the y-axes have differet scales for differet paels. J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01.

11 Katki et al. Page 11 NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript Figure 3. Cumulative risk of CIN2+ followig CIN1/egative colposcopy give subsequet (cosecutively) egative follow-up test(s), amog wome aged 25 ad older with atecedet HPV-positive/ASC-US or LSIL. The egative Pap test curves are for all Pap results aloe regardless of HPV test results ad the HPV egative test curves are for all HPV results aloe regardless of Pap test results. A egative cotest meas testig both HPV-egative ad Pap-egative. J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01.

12 Katki et al. Page 12 NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript Figure 4. Cumulative risk of CIN2+ followig CIN1/egative colposcopy give atecedet ASC-H/ HSIL+ (Blue lies) or AGC (Red lies) ad egative follow-up test, amog wome aged 25 ad older. The egative Pap test curves are for all Pap results aloe regardless of HPV test results ad the HPV egative test curves are for all HPV results aloe regardless of Pap test results. J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01.

13 Katki et al. Page 13 NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript Table 1 Distributio of worst histologic diagosis amog wome with CIN1/egative colposcopy aged 25 ad older, give atecedet Pap or cotest result that preceded colposcopy Total Worst histologic diagosis durig follow-up after CIN1/egative colposcopy Atecedet Pap ad HPV test result <CIN1, CIN1, CIN2, CIN3, AIS, Total CIN3 or AIS, Squamous carcioma, Adeocarcioma, Total cacers, Total 20,319 10,381 8, HPV-positive/ASC-US 9,936 4,901 4, LSIL 7,161 3,335 3, AGC 1,484 1, ASC-H 1, HSIL Note: Total cacers iclude ot oly squamous cell carcioma ad adeocarcioma but also adeosquamous carcioma, ad cervical cacer of ukow histology or histology urelated to HPV ifectio. The category Total CIN3 or AIS also icludes 1 woma with a diagosis that did ot differetiate betwee CIN3 ad AIS. HSIL+ icludes HSIL ad the few wome with SCC ad AIS Pap results. J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01.

14 Katki et al. Page 14 NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript Table 2 Distributio of worst histologic diagosis followig CIN1/egative colposcopy for wome age 25 ad older, give atecedet Pap or cotest result ad subsequet egative follow-up test results Total Worst histologic diagosis durig follow-up after CIN1/egative colposcopy Atecedet Pap ad HPV test result ad follow-up Pap result <CIN1, CIN1, CIN2, CIN3, AIS, Total CIN3 or AIS, Squamous carcioma, Adeocarcioma, Total cacers, Atecedet HPV+/ASCUS or LSIL Oe egative Pap 11,389 6,198 4, Two egative Paps 5,019 2,698 2, Oe egative HPV test 6,970 3,949 2, Two egative HPV tests 2,649 1,510 1, Oe egative cotest 5,939 3,408 2, Two egative cotests 1,963 1, Atecedet AGC Oe egative Pap 1,242 1, Oe egative HPV test 1, Oe egative cotest Atecedet ASC-H Oe egative Pap Oe egative HPV test Oe egative cotest Atecedet HSIL+ Oe egative Pap Oe egative HPV test Oe egative cotest Note: Total cacer icludes ot oly squamous cell carcioma ad adeocarcioma but also adeosquamous carcioma, ad cervical cacer of ukow histology or histology urelated to HPV ifectio. HSIL+ icludes HSIL ad the few wome with SCC ad AIS Paps. J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01.

15 Katki et al. Page 15 NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript Table 3 Bechmarkig CIN2+ risks for egative follow-up tests followig CIN1/egative colposcopy with atecedet HPV-positive/ASC-US or LSIL i wome aged 25 ad older, to CIN2+ risk thresholds implicitly used to determie cliical maagemet optios based o screeig Pap tests. Curret recommeded maagemet strategy based o Papaloe screeig Immediate colposcopy Implicit risk threshold: 5-year CIN2+ risk (%) 1 by baselie Papaloe a result LSIL: 16% 6-12 moth retur ASC-US: 6.9% Itermediate 3-year retur Pap-egative: 0.68% Wome with CIN1/egative colposcopy after HPV-positive/ASC-US or LSIL aged 25 ad older Follow-up with Pap-aloe a Pap result(s) 1 egative Pap 2 egative Paps a Follow-up Pap result(s) aloe (regardless of HPV test result) b Follow-up HPV test result(s) aloe (regardless of Pap result) 5-year CIN2+ risk after last test 5.4% 4.0% Follow-up with HPV testigaloe b HPV test result(s) 1 egative HPV test 2 egative HPV tests 5-year CIN2+ risk after last test 2.0% 1.8% Follow-up with cotestig HPV/Pap result(s) 1 egative cotest 2 egative cotests 1 Data preseted i: Katki HA, Schiffma M, Castle PE, Fetterma B, Poitras NE, Lorey T, et al. Bechmarkig CIN3+ risk as the basis for icorporatig HPV ad Pap cotestig ito cervical screeig ad maagemet guidelies J Low Geit Tract Dis I press. 5-year CIN2+ risk after last test 1.1% 1.0% J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01.

16 Katki et al. Page 16 NIH-PA Author Mauscript NIH-PA Author Mauscript NIH-PA Author Mauscript Table 4 Bechmarkig CIN2+ risks for egative follow-up tests followig CIN1/egative colposcopy with atecedet ASC-H/HSIL or AGC i wome aged 25 ad older, to CIN2+ risk thresholds implicitly used to determie cliical maagemet optios based o screeig Pap tests. Curret recommeded maagemet strategy based o Pap-aloe screeig Immediate colposcopy Implicit risk threshold: 5-year CIN2+ risk (%) 1 by baselie Pap-aloe a result LSIL: 16% 6-12 moth retur ASC-US: 6.9% 1 Wome with CIN1/egative colposcopy aged 25 ad older ASC-H/HSIL+ Pap result atecedet to colposcopy Follow-up result post-colposcopy 5-year CIN2+ risk after follow-up test egative Pap a 7.0% 1 egative HPV test b 4.4% AGC Pap result atecedet to colposcopy Follow-up result post-colposcopy 5-year CIN2+ risk after follow-up test Itermediate 1 egative cotest 2.2% 1 egative Pap a 1.7% 3-year retur Pap-egative: 0.68% 1 egative HPV test b 0.58% Note: For wome with a atecedet AGC, the cacer risk remaied high, justifyig maagig AGC similarly to ASC-H or HSIL+. Zero CIN2+ were detected amog wome with a atecedet AGC ad 1 egative follow-up cotest. a Follow-up Pap result(s) aloe (regardless of HPV test result) b Follow-up HPV test result(s) aloe (regardless of Pap result) 1 Data preseted i: Katki HA, Schiffma M, Castle PE, Fetterma B, Poitras NE, Lorey T, et al. Bechmarkig CIN3+ risk as the basis for icorporatig HPV ad Pap cotestig ito cervical screeig ad maagemet guidelies J Low Geit Tract Dis I press. J Low Geit Tract Dis. Author mauscript; available i PMC 2014 April 01.