Persistent HPV infection has a higher risk than most clinicians might think
Elfgren K, Elfström KM, Naucler P, Arnheim-Dahlström L, Dillner J. Management of women with human papillomavirus persistence: long-term follow-up of a randomized clinical trial. Am J Obstet Gynecol. 2017;216(3):264.e1-e7.
It is well known that most cases of cervical cancer arise from persistent HPV infection, with the highest percentage of cancers caused by high-risk types 16 or 18. What has been uncertain, however, is the actual degree of risk that persistent infection confers over time for the development of cervical intraepithelial neoplasia (CIN) or worse when a woman's repeated cytology reports are negative. In an analysis of a long-term double-blind, randomized, controlled screening study, Elfgren and colleagues showed that all women whose HPV infection persisted up to 7 years developed CIN grade 2 (CIN2+), while those whose infection cleared in that period, or changed genotype, had no precancerous lesions out to 13 years of follow-up.
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Details of the study
Between 1997 and 2000, 12,527 Swedish women between the ages of 32 and 38 years who were undergoing organized cervical cancer screening agreed to participate in a 1:1-randomized prospective trial to determine the benefit of screening with HPV and cytology (intervention group) compared with cytology screening alone (control group). However, brush sampling for HPV was performed even on women in the control group, with the samples frozen for later testing. All participants were identified in the Swedish National Cervical Screening Registry.
Women in the intervention group who initially tested positive for HPV but whose cytology test results were negative (n = 341) were invited to return a year later for repeat HPV testing; 270 women returned and 119 had type-specific HPV persistence. Of those with persistent infection, 100 agreed to undergo colposcopy; 111 women from the control group were randomly selected to undergo sham HPV testing and colposcopy, and 95 attended. Women with evident cytologic abnormalities received treatment per protocol. Those with negative cytology results were offered annual HPV testing thereafter, and each follow-up with documented type-specific HPV persistence led to repeat colposcopy. A comparable number of women from the control group had repeat colposcopies.
Although some women were lost to clinical follow-up throughout the trial, all 195 who attended the first colposcopy were followed for at least 5 years in the Swedish registry, and 191 were followed in the registry for 13 years. Of 102 women with known HPV persistence at baseline (100 in the treatment group; 2 in the randomly selected control group), 31 became HPV negative, 4 evidenced a switch in HPV type but cleared the initial infection, 27 had unknown persistence status due to missed HPV tests, and 40 had continuously type-specific persistence. Of note, persistent HPV16 infection seemed to impart a higher risk of CIN development than did persistent HPV18 infection.
All 40 participants with clinically verified continuously persistent HPV infection developed CIN2+ within 7 years of baseline documentation of persistence (FIGURE 1). Among the 27 women with unknown persistence status, risk of CIN2+ occurrence within 7 years was 50%. None of the 35 women who cleared their infection or switched HPV type developed CIN2+.
Cytology is a valuable tool, but it tells us only what is happening today. HPV testing is the crystal ball that tells us a patient's risk of having a precancerous CIN or cancer in the future. In this well-done randomized prospective trial by Elfgren and colleagues, 100% of women whose persistent HPV infection continued up to 7 years developed CIN2+ or worse. The unmistakable implication of this finding is the need for active follow-up for women with persistent HPV infection. Equally important is the finding that no women who cleared their initial infection developed CIN2+, a very reassuring outcome, and one we can share with patients whose HPV clears.
Read about HPV-cytology cotesting
