Longitudinal studies of human papillomavirus infection : with special reference to screening for cervical cancer and treatment of CIN

Aim: To study the natural history of Human Papillomavirus (HPV) infection in the general population and among women with acquired immunosuppression as well as to evaluate possible uses of human papillomavirus testing in cervical screening programs.

Study I: Women treated for cervical intraepithelial neoplasi (CIN) were analysed for presence of HPV DNA by PCR and for HPV antibodies by ELISA before and 16-27 months later. 78% of the women were positive for HPV DNA before treatment. At follow-up 4 women had recurrent CIN. Only these women were still HPV DNA positive and HPV antibody levels had declined, suggesting that effective CIN treatment is also effective for treating the underlying HPV infection.

Study II: 109 women treated for CIN were followed with repeated testing for cervical HPV DNA. 85% of the women were HPV DNA positive before treatment, but I year later only seven women (9%) were positive for the same HPV type. Most women had cleared their infection at 3 months, suggesting that HPV DNA testing may be useful as a rapid intermediate end-point for monitoring the efficacy of CIN treatments.

Study III: A population-based cohort of 500 women was tested for HPV DNA. All HPV DNA positive women and an equal amount of randomly chosen HPV DNA negative women, all with normal cytology, were tested again 5 years later. The HPV DNA clearance rate was 92%. Only a few HPV type 16 infections persisted. The study suggested that a single HPV DNA test would mostly detect self-limiting infections.

Study IV: The antibody response to four major HPVs was determined in a European multi-centre study of 222 HIV-positive women with a known interval of HIV-seroconversion. HPV seroprevalences were high, ranging from 44% for HPV33 to 18% for HPV73. Major determinants of HPV seropositivity were history of another STD and > 20 lifetime sexual partners. Ninety-one women were also followed with repeated testing for a median of 1.9 years. 33-50% of scropositive women reverted to seronegativity, suggesting an impaired ability to maintain the HPV antibody response.

Study V: The colposcopic and histopathologic findings among women with HPV DNA persistence, in comparison with population-based controls was evaluated in a multi-centre randomised trial of screening for persistence of HPV DNA within the organised cervical screening programme. Out of the 12.526 32-38 years old women that were enrolled, 100 women with HPV DNA persistence, but normal cytology, and 95 control women were examined by colposcopy. 59% of women with a persistent HPV infection, had an abnormal colposcopy. Histopathologically confirmed CIN grade 2 or 3 was found among 28/98 (29%) of women with HPV DNA persistence and among 2/93 controls.

Conclusions: Since HPV DNA is rapidly cleared after effective treatment of CIN, HPV testing could be useful for monitoring the short-term efficacy of treatment. The finding of an impaired ability of HIV-infected women to maintain a stable HPV antibody level could be relevant for future studies of duration of protection after prophylactic HPV vaccination. A majority of HPV infections in the general population will clear spontaneously. However, population-based screening for repeated HPV DNA postivity ("persistence") in addition to cytology might be of value to increase the program sensitivity for detection of high grade CIN.

List of scientific papers

I. Elfgren K, Bistoletti P, Dillner L, Walboomers JM, Meijer CJ, Dillner J (1996). Conization for cervical intraepithelial neoplasia is followed by disappearance of human papillomavirus deoxyribonucleic acid and a decline in serum and cervical mucus antibodies against human papillomavirus antigens. Am J Obstet Gynecol. 174(3): 937-42.
https://pubmed.ncbi.nlm.nih.gov/8633673

II. Elfgren K, Jacobs M, Walboomers JM, Meijer CJ, Dillner J (2002). Rate of human papillomavirus clearance after treatment of cervical intraepithelial neoplasia. Obstet Gynecol. 100(5 Pt 1): 965-71.
https://pubmed.ncbi.nlm.nih.gov/12423862

III. Elfgren K, Kalantari M, Moberger B, Hagmar B, Dillner J (2000). A population-based five-year follow-up study of cervical human papillomavirus infection. Am J Obstet Gynecol. 183(3): 561-7.
https://pubmed.ncbi.nlm.nih.gov/10992174

IV. Elfgren K, van Benthem B, Langendam MW, Dillner J (2003). High HPV 16, 18, 33 and 73 seroprevalences, but limited antibody stability over time in HIV infected women. [Submitted]

V. Elfgren K, Rylander E, Radberg T, Strander B, Strand A, Paajanen K, Sjoberg I, Ryd W, Silins I, Dillner J (2003). Colposcopic and histopathologic findings in women participating in population-based screening for HPV DNA persistence. [Manuscript]