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Re: Longitudinal study of human papillomavirus persistence and cervical intraepithelial neoplasia grade 2/3: critical role of duration of infection.

In the report by Rodriguez et al. (1), two important concepts regarding incident persistent human papillomavirus (HPV) infection and subsequent progression to cervical intraepithelial neoplasia (CIN)2+ among older women should be clarified to avoid misinterpretations of the data. The first of these two concepts concerns the rate of progression of new HPV persistent infections to CIN2+. The authors reported that “Newly detected HPV infections, regardless of the woman’s age at the time of first detection, were associated with very low absolute risk of subsequent CIN2+ diagnosis” (1; page 321). The authors cited positive predictive values (PPVs) and showed no real difference between PPVs in younger vs older women. We agree that the use of PPV, which is highly dependent on the prevalence of the disease being studied, is nevertheless adequate for showing agespecific rates of progression of new infections to CIN2+ because the prevalence of CIN2+ varies with age. Merck’s clinical trial studies (2–4) data show that the rate of progression of incident persistent HPV 16/18-related persistent infection to HPV 16/18-related CIN2+ in women 16–26 years old (2.6 per 100 person-years, 95% confidence interval [CI] = 2.0 to 3.3) is similar to that in women 27–45 years old (2.9 per 100 person-years, 95% CI = 1.9 to 4.3) with no statistically significant difference (O. M. Bautista, unpublished data), which is consistent with authors’ PPV data. The second, related concept concerns the intrinsic value of incident persistent HPV infection as predictor of and precursor to subsequent progression to CIN 2+. The authors concluded that “ . . . new infections typically do not progress to CIN 2 or worse disease in older women; thus, overall potential benefit of prophylactic vaccination or frequent HPV screening to prevent or detect new carcinogenic HPV infections at older ages is low.” (1; page 315) implying that in older women, the intrinsic value of persistent infection as a precursor to CIN2+ is lower compared with the intrinsic value of persistent infection as a precursor to CIN2+ in younger women. Although the authors’ PPV in older women is lower than that in younger women and seems to support their conclusion, the PPV is not sufficient to characterize the intrinsic value of new infections as a precursor of CIN2+ because PPV is confounded with the age-specific prevalence of CIN2+. The likelihood ratio positive (LR+) statistic, which is independent of disease prevalence (5), is a better metric for measuring the intrinsic value of incident persistent HPV infection in each age group as a predictor of and precursor to subsequent progression to CIN2+. Data presented in the paper do not allow for independent reader-verification of LR+ associated with age-specific incident HPV infection. In our studies (2–4), estimates of LR+ statistics associated with incident persistent HPV16/18-related infection as a predictor of subsequent progression to HPV16/18-related CIN 2+ are 5.5 (95 % CI = 4.2 to 7.1) in women 16–26 years old and 23.3 (95% CI = 15.6 to 34.5) in women 27–45 years old (O. M. Bautista, unpublished data). These data support the conclusion that the intrinsic value of persistent infection as a predictor of and precursor to subsequent progression to CIN 2+ is no worse in older women compared with younger women, contrary to the authors’ conclusion that new infections in older women typically do not progress to CIN2+. Incident persistent HPV infection is intrinsically predictive of subsequent progression to CIN2+ regardless of the age of the woman who acquired an incident persistent HPV infection. Younger women and older women differ in the attack rate of incident persistent infection and incident CIN2+. Data from our clinical studies are consistent with the authors’ data showing that attack rates decline with age. However, once a woman acquires an incident HPV infection, the rate of progression to CIN2+ is similar in younger and older women, as demonstrated in the authors’ PPV data. Intrinsically, incident persistent HPV infection is predictive of subsequent progression to CIN2+ regardless of age.