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CONDOM USE PROMOTES REGRESSION OF CERVICAL INTRAEPITHELIAL

NEOPLASIA AND CLEARANCE OF HUMAN PAPILLOMAVIRUS:

A RANDOMIZED CLINICAL TRIAL

Cornelis J.A. HOGEWONING1

, Maaike C.G. BLEEKER2

, Adriaan J.C. VAN DEN BRULE2

, Feja J. VOORHORST3

, Peter J.F. SNIJDERS2

,Johannes BERKHOF

3, Pieter J. WESTENEND4 and Chris J.L.M. MEIJER

2*1 Department of Gynaecology and Obstetrics, Albert Schweitzer Hospital, Dordrecht, the Netherlands2 Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands3 Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands4 Department of Pathology, Albert Schweitzer Hospital, Dordrecht, the Netherlands

Women with persistent HPV infections have increased risk of progressive CIN lesions. Transmission of HPV betweensexual partners might maintain viral infection and, conse-quently, may influence the clinical course of CIN. We inves-tigated the effect of condom use on regression of CIN lesionsand on clearance of HPV. Women with CIN and their malesexual partners were randomized for condom use (condomgroup n 72 and noncondom group n 76). They wereconservatively managed and followed every 3–6 months by

colposcopy, cytology and HPV testing by GP5/6 PCR.Baseline cervical biopsy specimens were taken. Median fol-low-up time for women was 15.2 months (range 3.0–85.4).Outcomes of interest were clinical regression of CIN at col-poscopy and clearance of HPV. Outcomes were assessed in64 women of the condom group and 61 women of the non-condom group. Women in the condom group showed a2-year cumulative regression rate of 53% vs. 35% in the non-condom group ( p 0.03). The 2-year cumulative rates of HPV clearance were 23% vs. 4%, respectively ( p 0.02).Although lower regression rates were found if women wereHPV-positive and had >CIN2 lesions at baseline, effects of condom use were found both in women with CIN1 and in

women with >CIN2 lesions. Condom use promotes regres-sion of CIN lesions and clearance of HPV.© 2003 Wiley-Liss, Inc.

Key words: cervical intraepithelial neoplasia; human papillomavi-

rus; condom use; clinical course

Persistent infection of the cervical epithelium with high-risk types of HPV plays a major role in the development, maintenanceand progression of CIN.1,2 HPV has been found in 99.7% of cervical cancers worldwide.3

Sexual intercourse is the primary mode for transmission oracquisition of HPV, and prevalence is related to many determi-nants involving sexual behavior characteristics.4– 6 Case-controlstudies of male sexual partners of women with cervical cancerhave shown a relation between male sexual behavior and cervicalcancer.7,8 The presence of HPV DNA in penile swabs conveyed a5-fold risk of cervical cancer to their wives.5 Studies on the risk factors of CIN supported a protective effect of condom use inwomen, emphasizing the venereal nature.9–11 Coker et al.12 found

that among high-risk HPV-positive women longer-duration barriermethod use was associated with a reduced risk of CIN. Manhartand Koutsky13 reported in a meta-analysis that data on effects of condom use preventing HPV infection and HPV-related conditionswere inconsistent. However, none of these studies was conductedexplicitly to assess the effectiveness of condoms at preventingHPV infection and HPV-related conditions.

Previously, we showed that flat penile lesions are associatedwith the presence of HPV and that regression is dependent on thepresence of HPV14 (see also Bleeker and Hogewoning, 2003,accompanying paper). Continuous transmission of HPV in sexualpartners having HPV-associated genital lesions might reduce thechance of viral clearance. In a randomized clinical trial, we inves-tigated the influence of condom use on the clinical course of

HPV-associated genital lesions and HPV infection in sexual part-ners. In the present report, we evaluate the effects of condom useon CIN regression and HPV clearance.

MATERIAL AND METHODS

Study population and design

Women referred to the colposcopy clinic of the Albert

Schweitzer Hospital, Dordrecht, the Netherlands, from January1995 to June 2002 were asked to bring in their male sexual partner.Eligible were women with an abnormal cervical smear (milddysplasia or worse) and/or cCIN and/or hCIN. Women were eval-uated for CIN by colposcopy and by histologic evaluation of cervical biopsy specimens at baseline. Cervical smears were takenfor cytology and HPV testing by PCR. The outline of the study wasverbally explained and written information given to couples whohad no other sexual partners. Willing couples returned within 2weeks to discuss the study protocol in detail, and additional ques-tions were answered. Both the period of condom use, i.e., onlyduring the study and for at least 3 months, and the instructions oncondom use, i.e., during genital–genital contact, were discussedwith participants. Latex condoms (Durex fetherlite; NetherlandsLRC, Leerdam, the Netherlands) with basic lubricant (withoutspermicidal and/or virus-inactivating substances) were given free,

to increase study compliance. Exclusion criteria were surgicaltreatment of the cervical lesion and regular condom use at baseline,i.e., using condoms for birth control. CIN2 and CIN3 lesions over

Abbreviations: cCIN, colposcopicly cervical intraepithelial neoplasia;CI, confidence interval; CIN, cervical intraepithelial neoplasia; EIA, en-zyme immunoassay; hCIN, histologicly cervical intraepithelial neoplasia;HPV, human papillomavirus; HR, hazard ratio; LLETZ, large-loop biopsyof the entire transformation zone; STD, sexually transmitted disease.

Grant sponsor: Dutch Prevention Fund/Zorg Onderzoek Nederland;Grant number: 28-2725.

This work is dedicated to Jan M.M. Walboomers, who passed away on2 February 2000. He was one of the principal investigators of this project.

The first 2 authors contributed equally to this work.

*Correspondence to: Department of Pathology, VU University MedicalCenter, PO Box 7057, 1007 MB, Amsterdam, the Netherlands.Fax: 31-020-444-2964. E-mail: [email protected]

Received 13 March 2003; Revised 1 July 2003; Accepted 18 July 2003

DOI 10.1002/ijc.11474

Int. J. Cancer: 107, 811–816 (2003)

© 2003 Wiley-Liss, Inc.

Publication of the International Union Against Cancer

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2 cervical quadrants were treated according to standard proto-cols. Irrespective of CIN grade at baseline, couples were random-ized for condom use in blocks of 2 if conservative management of

the CIN lesion was decided. Per block of 2 couples, the sequenceof condom and noncondom allocation was based on a table of random numbers. Colposcopic and cervical smears were repeatedafter 3, 6 and 12 months and subsequently every 6 months.Condom use was verbally verified at each visit by asking thefrequency of condom use failure. To minimize interference withthe natural course of CIN, a biopsy specimen was taken duringfollow-up only when progression of CIN lesions was suspected onthe basis of findings at colposcopy and/or cytology to justify theLLETZ procedure. Follow-up was ended if women were treated byLLETZ. Couples were asked to complete a questionnaire on life-style habits, including sexual behavior. Independently of eachother and in separate rooms, questionnaires were completed. Thisquestionnaire was introduced in 1999. The study protocol wasapproved by the ethics review board of the hospital (protocolCGE/95/238), and the couples signed informed consent before

enrollment.

Colposcopy

Before colposcopic evaluation, cervical smears were taken forcytologic and HPV testing. For HPV testing, a Cervex brush(Rovers Medical Devices, Oss, the Netherlands) was used tocollect cells from the cervix. The brush was placed in 5 ml of PBSsolution with 0.001% thimerosal (Merthiolate) (BDH, Poole, UK),and samples were sent to the laboratory and stored at 4°C untiltesting.15 Standard colposcopy was performed after application of 3% acetic acid solution and blinded of data from previous visits.Colposcopic characteristics such as acetowhiteness, mosaic, punc-tation, leukoplakia and atypical vessels were assessed and classi-fied according to the international terminology.16 Minor changes,

e.g., thin acetowhite epithelium, fine mosaic, fine punctation andthin leukoplakia, were noted as cCIN1 and major changes, e.g.,dense acetowhite epithelium, coarse mosaic, coarse punctation and

atypical vessels, as cCIN2 or cCIN3. Other diagnoses, e.g., squa-mous metaplasia, inflammatory changes, polyps or atrophicchanges, were also noted. An overview of the colposcopic impres-sion was drawn and categorized on the basis of the most atypicalsite: no cCIN, cCIN1, cCIN2 and cCIN3. Subsequently, colpo-scopic findings were documented by photographs. Photographswere reviewed by an experienced colposcopist blinded of anyclinical data. In case of discrepancies (10%), a consensus diag-nosis was made. Lesions were graded before linking these data oncondom use.

HPV testing

Processing and testing of cervical scrapings for HPV analysiswere performed as described previously at the Department of Pathology, VU University Medical Center.15 Samples were cen-trifuged and cell pellets resuspended in 1,000 l TRIS buffer. InPCR tests, aliquots of 10 l were used. The quality of the speci-men was tested by -globin PCR, and 14 high-risk (16, 18, 31, 33,35, 39, 45, 51, 52, 56, 58, 59, 66 and 68) and 6 low-risk (6, 11, 40,42, 43 and 44) HPV genotypes were identified by the clinicallyvalidated HPV GP5 /6 PCR EIA. Samples negative on both the-globin and HPV PCR tests were considered inadequate andexcluded.

Definitions of CIN regression and HPV clearance

Regression of the cCIN lesion was defined as 2 consecutive “nocCIN” diagnoses at colposcopy. Women were considered to havecleared the HPV infection when 2 consecutive negative HPV testswere obtained.

FIGURE 1 – Trial profile.

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Statistical analysis

Analyses for condom use were by intention to treat. Differencesbetween the condom and the noncondom groups were assessed by2 tests or independent t -tests. In survival analysis, the time pointof CIN regression and HPV clearance was taken as the midpointbetween the last positive and the first negative results. Kaplan-Meier curves, for regression of cCIN lesions and clearance of

HPV, were compared by means of 2-sided log-rank tests. Coxregression analyses were performed to calculate the HR and 95%CI, adjusted for condom use, HPV status, histologic CIN grade(either hCIN1 or hCIN2) and age (tertiles). HPV status wasdefined by the presence of HPV at baseline. HPV-positive womenwere stratified into HPV-16, other high-risk HPV or only low-risk HPV to assess whether CIN regression and/or HPV clearance wasrelated to HPV type. Interaction terms were added to the Coxmodel to assess whether the effect of condom use was related toHPV status or the hCIN grade of the lesions. Within the condomgroup, whether the effect was dependent on the duration of con-dom use was assessed. Therefore, Kaplan-Meier analyses wereperformed on women who still had colposcopic CIN or HPVpresent at 6 months and were stratified for condom use at this timepoint. Statistical significance was set at the 0.05 level. For statis-tical analyses, SPSS (Chicago, IL) version 9.0 software was used.

RESULTS

Characteristics of the study population

The trial profile is given in Figure 1. Of 255 couples selected forthe presence of CIN in the female partner, 17 were not willing toparticipate, 78 women were treated by LETTZ and 12 women wereexcluded due to regular condom use, leaving 148 women random-ized (condom group n 72 and noncondom group n 76).Women were excluded because of no colposcopic CIN ( n 9), nocolposcopic diagnosis (n 4) or loss to follow-up (n 10). Theremaining 125 women were followed: 64 in the condom group and61 in the noncondom group. Median follow-up time was 16.4(range 3.0–85.4) months in the condom group and 12.8 (range3.1–63.0) months in the noncondom group. Median duration of condom use was 6.0 (range 3.0–53.7) months, and failure to use

condoms was reported by 7 women with a median of 2 timesduring the period of condom use (range 1–5). Characteristics of both groups are shown in Table I. At baseline, colposcopic diag-noses were, in the condom group, cCIN1 (n 34), cCIN2 (n 29)and cCIN3 (n 1) and, in the noncondom group, cCIN1 (n 36),cCIN2 (n 24) and cCIN3 (n 1). Representative histologicdiagnoses of biopsy specimens were not available in 6 (9%)women of the condom group and 4 (7%) women of the noncondomgroup. Eight of them had cCIN1 lesions and 2 had a cCIN2 lesion.The remaining biopsies showed, in the condom group, no hCIN in8 (14%), hCIN1 in 18 (31%), hCIN2 in 31 (53%) and hCIN3 in 1(2%) and, in the noncondom group, no hCIN in 11 (19%), hCIN1in 25 (44%), hCIN2 in 19 (33%) and hCIN3 in 2 (4%). Histologicevaluation of cCIN1 lesions (n 62) showed no hCIN in 13(21%), hCIN1 in 31 (50%), hCIN2 in 17 (27%) and hCIN3 in 1(2%) biopsy specimens. Histologic evaluation of cCIN2 lesions

(n 51) showed no hCIN in 6 (12%), hCIN1 in 11 (22%), hCIN2in 32 (63%) and hCIN3 in 2 (4%) biopsy specimens. The 2 womenwith cCIN3 were included in the study because histologic speci-mens showed hCIN1 and hCIN2, respectively. Three women withhCIN3 lesions were included because their lesions were small (2cervical quadrants). At baseline, 2/64 (3%) cervical scrapes of thecondom group and 2/61 (3%) cervical scrapes of the noncondomgroup were inadequate for HPV testing, i.e., were negative in boththe -globin and HPV PCR tests. Of the remaining, 101 (84%)scrapes were positive for HPV: 54 (87%) of the condom group and47 (80%) of the noncondom group. Of the HPV-positive women,HPV-16 was found in 27 (50%) of the condom group and in 22(47%) of the noncondom group and other high-risk HPV (notHPV-16) was found in 26 (48%) and 22 (47%), respectively. Only

low-risk HPV was found in 1 (2%) HPV-positive woman of thecondom group and in 3 (6%) HPV-positive women of the noncon-dom group. Questionnaires were obtained from 51/125 (41%)women, 26/64 (41%) of the condom group and 25/61 (41%) of thenoncondom group. No statistical differences were found betweenthe condom and noncondom groups for smoking habits, age at firstsexual intercourse, number of sexual partners, number of noncon-dom sexual partners, history of STDs, other sexual partners lastyear, duration of the current relation, frequency of sexual inter-course and contraceptive use (Table I).

Regression of CIN

The 2-year cumulative regression rate of cCIN was 53% in thecondom group (n 57) vs. 35% in the noncondom group (n 51,log rank p 0.03; HR 3.1, 95% CI 1.4–7.1) (Fig. 1, Table II).Since regression was defined as 2 consecutive “no cCIN” diag-

FIGURE 2 – Effect of condom use on regression of CIN lesions (a)and clearance of HPV (b).

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noses, 17 women were excluded due to lack of follow-up data afterthey showed a normal colposcopy once. Age was not related toregression of CIN in our study population. Less regression of cCIN

was seen in HPV-positive women (HR 0.2, 95% CI 0.1–0.5)and in women with hCIN2 at baseline (HR 0.3, 95% CI0.1–0.7). In HPV-positive women, regression of CIN was notrelated to HPV type when stratified into HPV-16, other high-risk HPV or only low-risk HPV. The effect of condom use was notrelated to HPV status ( p 0.4) or hCIN grade at baseline ( p 0.8). Since the outcome variable for regression of cCIN wasdefined by colposcopy, analyses were also performed with inclu-sion of the cCIN grade instead of the hCIN grade defined atbaseline. Less regression of cCIN was observed in women withcCIN2 compared to women with cCIN1 at baseline (HR 0.3,95% CI 0.1–0.6, p 0.003). In women who still had cCIN lesionsat 6 months, no different regression rates were found duringfollow-up to 24 months in those who used condoms longer than 6

months (n 14) compared to those who used condoms for lessthan 6 months (n 15; log-rank p 0.6).

Clearance of HPV The 2-year cumulative rate of HPV clearance was 23% in the

condom group (n 53) vs. 4% in the noncondom group (n 38,log rank p 0.02; HR 12.1, 95% CI 1.5–97.2) (Fig. 2, Table II).Of the 125 women, 34 were excluded in the HPV clearanceanalyses since they were HPV-negative at baseline (n 20), theyhad cervical scrapes that were inadequate for HPV testing atbaseline and/or during follow-up (n 7) or there was no availablefollow-up data on HPV after they were HPV-negative once (n 7). No relation was found between clearance of HPV and age.Clearance of HPV was related to hCIN grade; i.e., less HPVclearance was found in women with hCIN2 compared to womenwith hCIN1 at baseline (HR 0.2, 95% CI 0.04 – 0.8). However,HPV clearance was not related to cCIN grade at baseline (HR

TABLE I – CHARACTERISTICS OF THE STUDY POPULATION

Number (%) Condom group

Number (%)Noncondom group

Number (%) p

Study subjects 125 64 (51) 61 (49)Age (mean, range, in years) 34.6 (19.1–54.7) 34.1 (19.1–54.7) 35.1 (22.5–52.6) 0.930.8 42 (34) 21 (33) 21 (34) 0.730.8–36.4 41 (33) 23 (36) 18 (30)

36.4 42 (34) 20 (31) 22 (36)Follow-up time (median, range, in months) 15.2 (3.0–85.4) 16.4 (3.0–85.4) 12.8 (3.1–63.0) 0.4HPV at baseline 0.6

Positive 101 (84) 54 (87) 47 (80) 0.3HPV-16 49 (49) 27 (50) 22 (47) 0.5Other high-risk HPV (not HPV-16) 48 (48) 26 (48) 22 (47)Only low-risk HPV 4 (4) 1 (2) 3 (6)Negative 20 (17) 8 (13) 12 (20)ND1 4 2 2

CIN grade at colposcopy 0.3CIN1 70 (56) 34 (53) 36 (59)CIN2 53 (42) 29 (45) 24 (39)CIN3 2 (2) 1 (2) 1 (2)

CIN grade at histology 0.2No biopsy 10 6 4No CIN 19 (17) 8 (14) 11 (19)CIN1 43 (37) 18 (31) 25 (44)CIN2 50 (43) 31 (53) 19 (33)

CIN3 3 (3) 1 (2) 2 (4)Characteristics obtained by questionnairesStudy subjects 51 (41) 26 (41) 25 (41) 1.0Smoking 0.1

No 25 (49) 16 (62) 9 (36)Yes 26 (51) 10 (38) 16 (64)Years (mean, range) 18.7 (7–35) 17.0 (10–25) 19.5 (7–35) 0.5Cigarettes per day (mean, range) 16.2 (2–30) 15.2 (2–30) 16.8 (5–30) 0.6

Oral contraceptive use 0.3No 23 (45) 14 (54) 9 (36)Yes 28 (55) 12 (46) 16 (64)

Age at first sexual intercourse (years, mean, range) 16.3 (13–21) 16.3 (13–21) 16.2 (13–21) 0.7History of STD 0.4

No 45 (88) 24 (92) 21 (84)Yes 6 (12) 2 (8) 4 (16)

Lifetime sexual partnersOverall (mean, range) 5.9 (1–30) 5.6 (1–15) 6.3 (1–30) 0.6Noncondom partners (mean, range) 3.9 (1–10) 4.3 (1–10) 3.6 (1–10) 0.3

Other sexual partner last year 0.5No 49 (96) 24 (92) 25 (100)Yes 2 (4) 2 (8) 0 (0)

Type of relationship 0.7Married/living together 46 (90) 24 (92) 22 (88)Living apart 5 (10) 2 (8) 3 (12)

Duration relation in years (mean/range) 9.2 (0.6–35) 9.7 (0.6–35) 8.7 (1–28) 0.7Frequency sexual Intercourse

Frequency per month (mean, range) 7.2 (0–22.5) 7.2 (0–22.5) 7.2 (1–22.5) 1.0Frequency last month (mean, range) 5.5 (0–20) 4.6 (0–20) 6.4 (1–20) 0.2

1Not be determined due to samples being inadequate for HPV testing. CIN grade (at colposcopy and histology) refers to diagnoses made atbaseline.

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0.4, 95% CI 0.1–1.7). In HPV-positive women, HPV clearancewas not related to HPV type when stratified into HPV-16, otherhigh-risk HPV or only low-risk HPV. hCIN grade at baselinehistology was not related to the effect of condom use on HPVclearance ( p 0.9). In women who still were HPV-positive after6 months, no different clearance rates were found in those whoused condoms longer than 6 months (n 17) compared to thosewho used condoms for less than 6 months (n 14, log-rank p 0.6).

DISCUSSION

In a randomized clinical study, performed in a non-STD clinic,125 women with cCIN were followed by colposcopy and HPVtesting. We found that condom use promotes regression of cCINand clearance of HPV. The 2-year cumulative regression rate forcCIN was 53% in the condom group vs. 35% in the noncondom

group ( p 0.03), and 2-year cumulative rates of HPV clearancewere 23% vs. 4%, respectively ( p 0.02). These beneficial effectsof condom usage were independent of hCIN grade.

One limitation of our study was that regression of CIN wasdefined by colposcopy and not verified by histology. Only baselinebiopsy specimens were taken for histopathologic diagnoses sincerepeated biopsies would interfere too much with the natural courseof the CIN lesion. To minimize this potential weakness, regressionof cCIN was defined as disappearance of the total cCIN lesion andevents were scored only in women with 2 consecutive “no cCIN”diagnoses. Our findings on concordance between the colposcopicand histopathologic diagnoses are in agreement with the positivepredictive rates reported by Hopman et al.17 They reported positivepredictive rates of the colposcopic impression to be 62% for noCIN, 43% for CIN1, 59% for CIN2 and 78% for CIN3.

Women with a negative HPV test at baseline showed moreregression of cCIN compared to women who were HPV-positive.This is in agreement with findings on the relation between HPV atbaseline and cytologic regression in women with abnormalsmears.18,19 In analogy, a shorter regression time of flat penilelesions was found in the absence of HPV, as reported in theaccompanying paper on male sexual partners of women with CIN.

Another limitation of our study is that the number of womenincluded is relatively small and women were not randomized byCIN grade. Compared to the noncondom group, a relatively highnumber of women with high-grade CIN were included in thecondom group, which might result in underestimation of the effectof condoms as the grade of the CIN lesion is an important prog-nostic factor for the regression of CIN.20 Analyses on the effects of

condoms, however, were adjusted for the most important risk factors (i.e., CIN grade and HPV status).

As characteristics of sexual behavior were collected in only 41%of women, adjustments for these factors could not be done prop-erly. However, no differences on sex-related factors betweengroups were found, as one would expect given the randomizeddesign of our study. Moreover, as data collection was time-se-lected, the women who filled out the questionnaires comprised arepresentative sample of the whole population. Therefore, weconclude that these factors did not influence our findings oncondom use. Current sex-related factors, especially frequency of sexual intercourse, might be relevant to assess the effect of con-dom use, though no differences were found among the couplesanalyzed. However, failure to use condoms, as was found in thecondom branch, might result in a less favorable effect of condomuse on CIN regression and HPV clearance. Beneficial effects of

condom use were found after a relatively short duration of use(median 6.0 months). We used a minimal duration of 3 months’condom use before randomization, though the maximum durationof condom use was not defined at baseline. An attractive, thoughhypothetical, explanation for our findings might be that condomsinterfere with continuous transmission of shed HPV between sex-ual partners. As a consequence, in individuals who benefit fromthis interference, the viral load would remain under a certaincritical threshold, allowing effective virus elimination by the im-mune system, thereby accelerating regression of the lesion. Non-interference in these individuals would, however, result in viralload levels that are sufficiently high to safeguard viral persistence.That viral load may be an important determinant in the observedphenomena is substantiated by another study, which demonstratedthat women with abnormal cytology and relatively low HPV-16loads had an increased chance of viral clearance and cytologic

regression.21

Since the viral load appears to be proportional to thesize and severity of lesions, a more marked effect of condom useis expected for smaller, less severe lesions that consequently havelower viral loads.22 Indeed, the effect was much more pronouncedfor penile than for cervical lesions. The former are generallysmaller and less severe and have viral loads that are 5- to 10-foldlower than in their cervical counterparts (data not shown). Incontrast, individuals with high viral loads are unlikely to respondto condom use since maintenance of the lesion would not dependon exposure to virus of the partner. Because women with large andsevere lesions (cCIN2 on 2 quadrants) were treated for ethicalreasons, only women with relatively small lesions, having mostlikely lower viral load values, were selected for study. Therefore,an attractive subject of future studies may be to determine the HPV

TABLE II – PROGNOSTIC FACTORS FOR CIN REGRESSION AND HPV CLEARANCE

CIN regression HPV clearance

Number HR (95% CI) p Number HR (95% CI) p

Condom useNo 48 1.0 36 1.0Yes 50 3.1 (1.4–7.1) 0.006 48 12.1 (1.5–97.2) 0.01

HPV

Negative 13 1.0 NAPositive 85 0.2 (0.1–0.5) 0.0003 NAHPV-16 44 1.0 44 1.0Other high-risk HPV (not HPV-16) 38 1.3 (0.5–3.5) 0.6 37 3.1 (0.6–14.6) 0.2Only low-risk HPV 3 2.0 (0.03–2.3) 0.6 3 01 1.0

Histologic CIN gradeCIN1 48 1.0 38 1.0CIN2 50 0.3 (0.1–0.7) 0.01 46 0.2 (0.04–0.8) 0.02

Age (years)30.8 30 1.0 27 1.030.8–36.4 35 1.6 (0.6–4.3) 0.3 28 0.4 (0.04–4.0) 0.436.4 33 1.3 (0.5–3.6) 0.6 29 2.9 (0.8–11.7) 0.1

Adjustments were made for all other factors in the table. NA, not applicable.– 1Could not be calculated since no clearance was observed inthis category.

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