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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).
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.
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%).
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.
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.
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 |
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.
† 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;
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