PDF
ePub
Citation
Print
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
1. Jung KW, Won YJ, Kong HJ, Lee ES. Community of Population-Based Regional Cancer Registries. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2015. Cancer Res Treat. 2018; 50:303–16.
2. Trottier H, Franco EL. Human papillomavirus and cervical cancer: burden of illness and basis for prevention. Am J Manag Care. 2006; 12:S462–72.
3. Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, et al. A review of human carcinogens–part B: biological agents. Lancet Oncol. 2009; 10:321–2.
4. International Agency for Research on Cancer. A review of human carcinogens. Part B: Biological agents [Internet]. Lyon: International Agency for Research on Cancer;2012. [cited 2018 Feb 20]. Available from:. http://monographs.iarc.fr/ENG/Monographs/vol100B/index.php.
5. de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer. 2017; 141:664–70.
6. Wang L, Wang P, Ren Y, Du J, Jiang J, Jia X, et al. Prevalence of high-risk human papillomavirus (HR-HPV) genotypes and multiple infections in cervical abnormalities from Northern Xinjiang, China. PLoS One. 2016; 11:e0160698.
7. Cutts FT, Franceschi S, Goldie S, Castellsague X, de Sanjose S, Garnett G, et al. Human papillomavirus and HPV vaccines: a review. Bull World Health Organ. 2007; 85:719–26.
8. Wheeler CM. Natural history of human papillomavirus infections, cytologic and histologic abnormalities, and cancer. Obstet Gynecol Clin North Am. 2008; 35:519–36.
9. Lee WC, Lee SY, Koo YJ, Kim TJ, Hur SY, Hong SR, et al. Establishment of a Korea HPV cohort study. J Gynecol Oncol. 2013; 24:59–65.
10. Travassos AG, Netto E, Xavier-Souza E, Nóbrega I, Adami K, Timbó M, et al. Predictors of HPV incidence and clearance in a cohort of Brazilian HIV-infected women. PLoS One. 2017; 12:e0185423.
11. Huh WK, Ault KA, Chelmow D, Davey DD, Goulart RA, Garcia FA, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Gynecol Oncol. 2015; 136:178–82.
12. Trottier H, Mahmud S, Costa MC, Sobrinho JP, Duarte-Franco E, Rohan TE, et al. Human papillomavirus infections with multiple types and risk of cervical neoplasia. Cancer Epidemiol Biomarkers Prev. 2006; 15:1274–80.
13. Munagala R, Donà MG, Rai SN, Jenson AB, Bala N, Ghim SJ, et al. Significance of multiple HPV infection in cervical cancer patients and its impact on treatment response. Int J Oncol. 2009; 34:263–71.
14. Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsagué X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003; 348:518–27.
15. Kay P, Soeters R, Nevin J, Denny L, Dehaeck CM, Williamson AL. High prevalence of HPV 16 in South African women with cancer of the cervix and cervical intraepithelial neoplasia. J Med Virol. 2003; 71:265–73.
16. Crosbie EJ, Einstein MH, Franceschi S, Kitchener HC. Human papillomavirus and cervical cancer. Lancet. 2013; 382:889–99.
17. Chan PK. Human papillomavirus type 58: the unique role in cervical cancers in East Asia. Cell Biosci. 2012; 2:17.
18. Bao YP, Li N, Smith JS, Qiao YL. ACCPAB members. Human papillomavirus type distribution in women from Asia: a meta-analysis. Int J Gynecol Cancer. 2008; 18:71–9.
19. Clifford GM, Smith JS, Plummer M, Muñoz N, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer. 2003; 88:63–73.
20. Brickman C, Palefsky JM. Human papillomavirus in the HIV-infected host: epidemiology and pathogenesis in the antiretroviral era. Curr HIV/AIDS Rep. 2015; 12:6–15.
21. Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection. Vaccine. 2006; 24(Suppl 1):S1–15.
22. Min KJ, Lee JK, Lee S, Kim MK. Alcohol consumption and viral load are synergistically associated with CIN1. PLoS One. 2013; 8:e72142.
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;
XML Download