Journal List > J Gynecol Oncol > v.30(3) > 1148321

Park, Kim, Hwang, Cho, Jeong, Seong, Lee, Hur, Kee, Seong, and Ki: Risk of cervical dysplasia among human papillomavirus-infected women in Korea: a multicenter prospective study

Abstract

Objective

Human papillomavirus (HPV) infection is the most important risk factor for cervical cancer, which progresses from precursor lesions with no symptom if left untreated. We compared the risk of cervical dysplasia among HPV-positive Korean women based on HPV types and infection patterns.

Methods

We observed participants of a 5-year multicenter prospective cohort study, comprising HPV-positive women with either atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion of the cervix at their enrollment. Follow-ups, comprising cytology and HPV DNA testing results, were included in the final analysis. Incidence was calculated for each infection pattern (persistent infection, incidental infection, and clearance). To investigate cervical dysplasia risk, we used Cox proportional hazard models adjusted for variables that were significantly different among infection patterns. From April 2010 to September 2017, 71 of 1,027 subjects developed cervical dysplasia more severe than high-grade squamous intraepithelial lesion of the cervix.

Results

Of these 71 subjects, persistent infection, incidental infection, and clearance were noted in 30, 39, and 2 individuals, respectively. Based on changes in DNA results during follow-up, cumulative incidence was 27.2%, 10.4%, and 0.5% for persistent infection, incidental infection, and clearance, respectively. Compared to clearance, the adjusted hazard ratios for cervical dysplasia were 51.6 and 24.1 for persistent and incidental infections, respectively (p<0.001).

Conclusion

Individuals persistently infected with the same HPV types during the follow-up period had the highest risk of severe cervical dysplasia. Hence, it is necessary to monitor HPV types and infection patterns to prevent severe cervical precancerous lesions.

References

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Fig. 1.
Examples of infection patterns and their definitions. The symbols (eg. diamond, square, or circle) stand for different HPV genotype detected at the time of visit, and the notation of (−) stands for being negative without detecting any of HPV genotype. HPV, human papillomavirus.
jgo-30-e50f1.tif
Fig. 2.
Distribution of HPVs among ASCUS or LSIL cases. ASCUS, atypical squamous cells of undetermined significance; HPV, human papillomavirus; LSIL, low-grade squamous intraepithelial lesion. * Detailed percentages of high-risk HPVs: HPV-16 (9.8%), HPV-58 (8.7%), HPV-56 (7.8%), HPV-53 (7.7%), HPV-52 (6.5%), HPV-39 (5.6%), HPV-68 (5.3%), HPV-51 (4.9%), HPV-18 (4.4%), HPV-66 (4.1%), HPV-35 (2.5%), HPV-31 (2.3%), HPV-33 (2.0%), HPV-59 (2.0%), HPV-45 (1.5%), HPV-82 (0.6%), HPV-69 (0.3%), HPV-26 (0.2%), and HPV-73 (0.1%).
jgo-30-e50f2.tif
Fig. 3.
Cumulative incidence of cervical dysplasia based on HPV infection patterns during follow-up in the Korea HPV cohort, 2010–2017. HPV, human papillomavirus.
jgo-30-e50f3.tif
Table 1.
Epidemiologic characteristics of study subjects based on HPV infection patterns, the Korea HPV cohort 2010–2017
Variables All (n=1,027) Persistent infection (n=144) Incidental infection (n=474) Clearance (n=409) p-value*
Follow-up (yr) 3.06±1.54 3.01±1.37 2.63±1.56 3.58±1.41 <0.001
Age (yr) 40.57±9.64 42.93±9.90 40.58±9.96 39.73±9.04 0.003
Age group         0.001
 20–29 167 (16.26) 18 (12.50) 86 (18.14) 63 (15.40)  
 30–39 297 (28.92) 33 (22.92) 122 (25.74) 142 (34.72)  
 40–49 350 (34.08) 51 (35.42) 159 (33.54) 140 (34.23)  
 ≥50 213 (20.74) 42 (29.17) 107 (22.57) 64 (15.65)  
BMI 21.77±2.81 21.97±2.82 21.75±2.76 21.72±2.85 0.637
Marital status         0.024
 Co-habitation 650 (63.35) 102 (71.33) 277 (58.44) 271 (66.26)  
 Separation 123 (11.99) 14 (9.79) 68 (14.35) 41 (10.02)  
 Single 253 (24.66) 27 (18.88) 129 (27.22) 97 (23.72)  
Education         0.184
 ≤highschool level 408 (39.73) 66 (45.83) 190 (40.08) 152 (37.16)  
 ≥college level 619 (60.27) 78 (54.17) 284 (59.92) 257 (62.84)  
Job         0.356
 Manager/head 250 (24.34) 32 (22.22) 118 (24.89) 100 (24.45)  
 Professionals 186 (18.11) 28 (19.44) 78 (16.46) 80 (19.56)  
 Business/service 211 (20.55) 24 (16.67) 108 (22.78) 79 (19.32)  
 Housekeeping 331 (32.23) 53 (36.81) 142 (29.96) 136 (33.25)  
 Unemployed/student 49 (4.77) 7 (4.86) 28 (5.91) 14 (3.42)  
Monthly income ($)         0.219
 <2,000 133 (12.95) 20 (13.89) 64 (13.50) 49 (11.98)  
 2,000–5,000 448 (43.62) 66 (45.83) 208 (43.88) 174 (42.54)  
 ≥5,000 382 (37.20) 50 (34.72) 164 (34.60) 168 (41.08)  
 Don't know 64 (6.23) 8 (5.56) 38 (8.02) 18 (4.40)  
Smoking         0.310
 No 881 (85.78) 128 (88.89) 399 (84.18) 354 (86.55)  
 Yes 146 (14.22) 16 (11.11) 75 (15.82) 55 (13.45)  
Drinking         0.041
 No 244 (23.73) 41 (28.47) 103 (21.73) 100 (24.51)  
 Not currently (yes) 64 (6.24) 5 (3.47) 24 (5.06) 35 (8.58)  
 Currently (yes) 718 (69.98) 98 (68.06) 347 (73.21) 273 (66.91)  
Regular exercise          
 No 583 (56.77) 75 (52.08) 262 (55.27) 246 (60.15)  
 Yes 444 (43.23) 69 (47.92) 212 (44.73) 163 (39.85)  
Pregnancy         0.437
 No 224 (21.81) 27 (18.75) 111 (23.42) 86 (21.03)  
 Yes 803 (78.19) 117 (81.25) 363 (76.58) 323 (78.97)  
  No. of offspring(s)         0.094
   None 93 (11.58) 15 (12.82) 43 (11.85) 35 (10.84)  
   1 188 (23.41) 18 (15.38) 77 (21.21) 93 (28.79)  
   2 429 (53.42) 68 (58.12) 198 (54.55) 163 (50.46)  
   3+ 93 (11.58) 16 (13.68) 45 (12.40) 32 (9.91)  
Menopause         0.001
 No 851 (82.94) 106 (73.61) 390 (82.28) 355 (87.01)  
 Yes 175 (17.06) 38 (26.39) 84 (17.72) 53 (12.99)  
Contraceptive use         0.908
 No 633 (61.64) 91 (63.19) 292 (61.60) 250 (61.12)  
 Yes 394 (38.36) 53 (36.81) 182 (38.40) 159 (38.88)  
Oral contraceptive use         0.011
 No 861 (83.84) 127 (88.19) 380 (80.17) 354 (86.55)  
 Yes 166 (16.16) 17 (11.81) 94 (19.83) 55 (13.45)  
Cumulative No. of sex partner(s)         0.049
 1 407 (39.71) 68 (47.22) 173 (36.58) 166 (40.69)  
 2–3 368 (35.90) 44 (30.56) 164 (34.67) 160 (39.22)  
 4–5 157 (15.32) 22 (15.28) 80 (16.91) 55 (13.48)  
 6+ 61 (5.95) 7 (4.86) 38 (8.03) 16 (3.92)  
No response 32 (3.12) 3 (2.08) 18 (3.81) 11 (2.70)  
HPV vaccination         0.651
 No 752 (73.22) 110 (76.39) 345 (72.78) 297 (72.62)  
 Yes 275 (26.78) 34 (23.61) 129 (27.22) 112 (27.38)  
  No. of HPV vaccination         0.568
   1 53 (5.16) 8 (5.56) 20 (4.22) 25 (6.11)  
   2 40 (3.89) 7 (4.86) 20 (4.22) 13 (3.18)  
   3 182 (17.72) 19 (13.19) 89 (18.78) 74 (18.09)  

Data are presented as the mean±standard deviation for continuous variables and number (percentage) for categorical variables. BMI, body mass index; HPV, human papillomavirus.

* p-values were obtained by using the analysis of variance test for continuous variables and the χ2test for categorical variables; p<0.05 at significance in bold letters;

Age group of ≥50 included 3 subjects aged 60 years;

Smoking status (yes) refers to a person who has smoked 100 cigarettes in her lifetime.

Table 2.
Incidence rate of cervical dysplasia per 1,000 person-years (n=71), the Korea HPV cohort 2010–2017
Covariates* HPV infection patterns (No. per 1,000 person-years)
Persistent infection (n=30) Incidental infection (n=39) ) Clearance (n=2)
Incidence of cervical dysplasia 76.2 31.2 1.4
Age group (yr)      
 20–29 75.4 21.9 4.8
 30–39 46.3 29.9 2.0
 40–49 76.6 50.9 0
 ≥50 62.2 13.1 0
Marital status      
 Co-habitation 65.9 38.1 0
 Separation 93.3 24.6 0
 Single 61.9 20.8 6.1
Drinking experience      
 Currently (yes) 78.1 25.8 0
 Not currently (yes) 0 111.5 0
 No 56.5 35.2 5.7
Menopause      
 Yes 56.4 17.0 0
 No 74.4 34.6 1.6
Oral contraceptive use      
 Yes 141.1 11.3 0
 No 61.4 34.2 1.6
Cumulative number of sex partner(s)      
 1 59.0 43.5 0
 2–3 81.4 25.2 1.8
 4–5 74.2 18.9 5.4
 6+ 0 21.3 0

* List of variables that were significantly different between infection patterns (Table 1, p>0.05) and were used for adjustment in the Cox proportional hazard models (Table 3).

Table 3.
HRs for the development of cervical dysplasia among HPV-positive women, the Korea HPV cohort 2010–2017
HPV infection patterns* Subjects CIN 2+ Crude Adjusted
HR 95% CI HR 95% CI
Clearance 409 2 1.0      
Incidental infection 474 39 21.5 5.1–88.9 24.1 5.7–100.2
 Low-risk HPV detected at last visit 100 3 1.7 0.1–18.6 1.7 0.1–19.3
 High-risk HPV detected at last visit 238 35 40.9 9.8–169.8 47.2 11.2–197.6
  Single infection 196 27 38.1 9.1–160.3 44.6 10.5–188.5
  Multiple infection 42 8 54.1 11.4–254.7 61.1 12.6–294.8
  High/low-risk HPV detected at last visit (mixed) 136 1 8.2 1.3–49.1 1.8 0.2–19.3
Persistent infection 144 30 47.0 11.2–196.8 51.6 12.2–217.5
 Persistent with high-risk HPV 126 29 51.8 12.3–217.1 57.1 13.5–240.8
  Single infection 77 17 49.1 11.3–212.6 52.9 12.0–232.1
  Multiple infection 49 12 56.2 12.5–251.0 63.5 14.1–285.3
   HPV type 16/18 31 10 74.2 16.2–338.8 83.0 17.6–390.1
    Single infection 17 6 80.9 16.3–400.8 77.2 14.6–405.8
    Multiple infection 14 4 66.1 12.1–360.9 95.1 16.8–536.9
   HPV type 50s 60 10 38.4 8.4–175.2 42.3 9.1–195.0
    Single infection 40 7 40.7 8.4–195.7 44.8 9.1–218.5
    Multiple infection 20 3 34.0 5.6–203.4 36.7 6.0–223.3
   Other types 35 9 54.8 11.8–253.7 61.6 13.2–287.1
    Single infection 20 4 40.2 7.3–219.6 49.2 8.8–274.0
    Multiple infection 15 5 77.3 14.9–398.5 77.2 14.8–401.9
 Persistent with low-risk HPV 18 1 12.5 1.1–137.5 13.0 1.1–144.9

CI, confidence interval; CIN, cervical intraepithelial neoplasia; CIN 2+, more severe than cervical intraepithelial neoplasia 2; HPV, human papillomavirus; HR, hazard ratio.

* The definition of HPV infection patterns can be found in Fig. 1;

Low-risk HPV including 9 HPV types including HPV-6, HPV-11, HPV-40, HPV-42, HPV-43, HPV-44, HPV-54, HPV-61, and HPV-70 and high-risk HPV including 19 HPV types including HPV-16, HPV-18, HPV-26, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-53, HPV-56, HPV-58, HPV-59, HPV-66, HPV-68, HPV-69, HPV-73, and HPV-82;

Adjustment for covariates including age, marital status, drinking, menopause, oral contraceptive, and cumulative number of sex partners.

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