Human papillomavirus type 18 DNA load and 2-year cumulative diagnoses of cervical intraepithelial neoplasia grades 2-3

Abstract

Background: The clinical relevance of the amount of human papillomavirus type 18 (HPV18) DNA in cervical tissue (ie, HPV18 DNA load) is unknown.

Methods: Study subjects were 303 women who were HPV18 positive at enrollment into the Atypical Squamous Cells of Undetermined Significance (ASC-US) and Low-Grade Squamous Intraepithelial Lesion (LSIL) Triage Study. HPV18 DNA load, expressed as copies of HPV18 per nanogram of cellular DNA, at enrollment was quantitatively measured. Subjects were followed up semiannually for a period of 2 years for detection of cervical intraepithelial neoplasia 2-3 (CIN2-3). A linear regression model was used to examine associations of CIN2-3 with HPV18 DNA load. All statistical tests were two-sided.

Results: CIN2-3 was confirmed in 92 of 303 (30.4%) HPV18-positive women. Among women without CIN2-3, HPV18 DNA load was positively associated with increasing severity of cervical cytology at enrollment (Ptrend < .001). However, among those with CIN2-3, HPV18 DNA load was not associated with severity of cervical cytology at enrollment (Ptrend = .33). The ratios of geometric means of HPV18 DNA load at enrollment among women with CIN2-3, relative to those without, were 6.06 (95% confidence interval [CI] = 0.31 to 117.92) for those with normal cytology at enrollment, 0.50 (95% CI = 0.10 to 2.44) for those with ASC-US, 0.11 (95% CI = 0.03 to 0.46) for those with LSIL, and 0.07 (95% CI = 0.01 to 0.80) for those with high-grade squamous intraepithelial lesion (HSIL). After adjusting for age and coinfection with other high-risk HPVs, a statistically significant association of lower HPV18 DNA load with CIN2-3 was observed among women with LSIL or HSIL at enrollment (P = .02). Within the 2-year period, HPV18 DNA load was unrelated to the timing of CIN2-3 diagnosis. Overall results were similar when the outcome was CIN3.

Conclusions: HPV18 DNA load was higher for women with LSIL or HSIL at enrollment with no evidence of CIN2-3 during the 2-year follow-up period than it was for women with CIN2-3. Thus, testing for high levels of HPV18 DNA does not appear to be clinically useful.

Figure 1

Geometric means (squares) and 95% confidence intervals (CIs; upper and lower bound) of human papillomavirus (HPV) type 18 DNA load at enrollment between women with (dashed line) and without (solid line) cervical intraepithelial neoplasia grades 2–3 (CIN2–3) during the 2-year study period. Among women without CIN2–3, the geometric mean of HPV18 E7 copy number per nanogram of cellular DNA was 522 (95% CI = 172 to 1598) for those with normal cytology, 9309 (95% CI = 4078 to 21 251) for those with atypical squamous cells of undetermined significance (ASC-US), 28 045 (95% CI = 13 900 to 56 621) for those with low-grade squamous intraepithelial lesion (LSIL), and 189 409 (95% CI = 28 976 to 1 238 112) for those with high-grade squamous intraepithelial lesion (HSIL) at enrollment (P_trend < .001); the corresponding values among women with CIN2–3 were 3166 (95% CI = 741 to 13,534), 4623 (95% CI = 1050 to 20 350), 3151 (95% CI = 881 to 11 277), and 12 891 (95% CI = 3280 to 50 672), respectively (P_trend < .33). P values (two-sided) were calculated with a trend test.